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1. Bramwell-Hill modeling for local aortic pulse wave velocity estimation: a validation study with velocity-encoded cardiovascular magnetic resonance and invasive pressure assessment

Author: Westenberg Jos JM, van Poelgeest Eveline P, Steendijk Paul, Grotenhuis Heynric B, Jukema JW, and de Roos Albert
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Abstract Background The Bramwell-Hill model describes the relation between vascular wall stiffness expressed in aortic distensibility and the pulse wave velocity (PWV), which is the propagation speed of the systolic pressure wave through the aorta. The main objective of this study was to test the validity of this model locally in the aorta by using PWV-assessments based on in-plane velocity-encoded cardiovascular magnetic resonance (CMR), with invasive pressure measurements serving as the gold standard. Methods Seventeen patients (14 male, 3 female, mean age ± standard deviation = 57 ± 9 years) awaiting cardiac catheterization were prospectively included. During catheterization, intra-arterial pressure measurements were obtained in the aorta at multiple locations 5.8 cm apart. PWV was determined regionally over the aortic arch and locally in the proximal descending aorta. Subsequently, patients underwent a CMR examination to measure aortic PWV and aortic distention. Distensibility was determined locally from the aortic distension at the proximal descending aorta and the pulse pressure measured invasively during catheterization and non-invasively from brachial cuff-assessment. PWV was determined regionally in the aortic arch using through-plane and in-plane velocity-encoded CMR, and locally at the proximal descending aorta using in-plane velocity-encoded CMR. Validity of the Bramwell-Hill model was tested by evaluating associations between distensibility and PWV. Also, theoretical PWV was calculated from distensibility measurements and compared with pressure-assessed PWV. Results In-plane velocity-encoded CMR provides stronger correlation (p = 0.02) between CMR and pressure-assessed PWV than through-plane velocity-encoded CMR (r = 0.69 versus r = 0.26), with a non-significant mean error of 0.2 ± 1.6 m/s for in-plane versus a significant (p = 0.006) error of 1.3 ± 1.7 m/s for through-plane velocity-encoded CMR. The Bramwell-Hill model shows a significantly (p = 0.01) stronger association between distensibility and PWV for local assessment (r = 0.8) than for regional assessment (r = 0.7), both for CMR and for pressure-assessed PWV. Theoretical PWV is strongly correlated (r = 0.8) with pressure-assessed PWV, with a statistically significant (p = 0.04) mean underestimation of 0.6 ± 1.1 m/s. This theoretical PWV-estimation is more accurate when invasively-assessed pulse pressure is used instead of brachial cuff-assessment (p = 0.03). Conclusions CMR with in-plane velocity-encoding is the optimal approach for studying Bramwell-Hill associations between local PWV and aortic distensibility. This approach enables non-invasive estimation of local pulse pressure and distensibility.
Published: 2012
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2. Life expectancy associated with different ages at diagnosis of type 2 diabetes in high-income countries: 23 million person-years of observation

Author: Kaptoge, S, Seshasai, SRK, Sun, L, Walker, M, Bolton, T, Spackman, S, Ataklte, F, Willeit, P, Bell, S, Burgess, S, Pennells, L, Altay, S, Assmann, G, Ben-Shlomo, Y, Best, LG, Björkelund, C, Blazer, DG, Brenner, H, Brunner, EJ, Dagenais, GR, Cooper, JA, Cooper, C, Crespo, CJ, Cushman, M, D'Agostino, RB, Sr, Daimon, M, Daniels, LB, Danker, R, Davidson, KW, de Jongh, RT, Donfrancesco, C, Ducimetiere, P, Elders, PJM, Engström, G, Ford, I, Gallacher, I, Bakker, SJL, Goldbourt, U, de La Cámara, G, Grimsgaard, S, Gudnason, V, Hansson, PO, Imano, H, Jukema, JW, Kabrhel, C, Kauhanen, J, Kavousi, M, Kiechl, S, Knuiman, MW, Kromhout, D, Krumholz, HM, Kuller, LH, Laatikainen, T, Lowler, DA, Meyer, HE, Mukamal, K, Nietert, PJ, Ninomiya, T, Nitsch, D, Nordestgaard, BG, Palmieri, L, Price, JF, Ridker, PM, Sun, Q, Rosengren, A, Roussel, R, Sakurai, M, Salomaa, V, Schöttker, B, Shaw, JE, Strandberg, TE, Sundström, J, Tolonen, H, Tverdal, A, Verschuren, WMM, Völzke, H, Wagenknecht, L, Wallace, RB, Wannamethee, SG, Wareham, NJ, Wassertheil-Smoller, S, Yamagishi, K, Yeap, BB, Harrison, S, Inouye, M, Griffin, S, Butterworth, AS, Wood, AM, Thompson, SG, Sattar, N, Danesh, J, Di Angelantonio, E, Tipping, RW, Russell, S, Johansen, M, Bancks, MP, Mongraw-Chaffin, M, Magliano, D, Barr, ELM, Zimmet, PZ, Whincup, PH, Willeit, J, Leitner, C, Lawlor, DA, Elwood, P, Sutherland, SE, Hunt, KJ, Selmer, RM, Haheim, LL, Ariansen, I, Tybjaer-Hansen, A, Frikkle-Schmidt, R, Langsted, A, Lo Noce, C, Balkau, B, Bonnet, F, Fumeron, F, Pablos, DL, Ferro, CR, Morales, TG, Mclachlan, S, Guralnik, J, Khaw, KT, Holleczek, B, Stocker, H, Nissinen, A, Vartiainen, E, Jousilahti, P, Harald, K, Massaro, JM, Pencina, M, Lyass, A, Susa, S, Oizumi, T, Kayama, T, Chetrit, A, Roth, J, Orenstein, L, Welin, L, Svärdsudd, K, Lissner, L, Hange, D, Mehlig, K, Tilvis, RS, Dennison, E, Westbury, L, Norman, PE, Almeida, OP, Hankey, GJ, Hata, J, Shibata, M, Furuta, Y, Bom, MT, Rutters, F, Muilwijk, M, Kraft, P, Lindstrom, S, Turman, C, Kiyama, M, Kitamura, A, Gerber, Y, Salonen, JT, van Schoor, LN, van Zutphen, EM, Melander, O, Psaty, BM, Blaha, M, de Boer, IH, Kronmal, RA, Grandits, G, Shin, H-C, Albertorio, JR, Gillum, RF, Hu, FB, Humphries, S, Hill- Briggs, F, Vrany, E, Butler, M, Schwartz, JE, Iso, H, Amouyel, P, Arveiler, D, Ferrieres, J, Gansevoort, RT, de Boer, R, Kieneker, L, Trompet, S, Kearney, P, Cantin, B, Després, JP, Lamarche, B, Laughlin, G, McEvoy, L, Aspelund, T, Thorsson, B, Sigurdsson, G, Tilly, M, Ikram, MA, Dorr, M, Schipf, S, Fretts, AM, Umans, JG, Ali, T, Shara, N, Davey-Smith, G, Can, G, Yüksel, H, Özkan, U, Nakagawa, H, Morikawa, Y, Ishizaki, M, Njølstad, I, Wilsgaard, T, Mathiesen, E, Buring, J, Cook, N, Arndt, V, Rothenbacher, D, Manson, J, Tinker, L, Shipley, M, Tabak, AG, Kivimaki, M, Packard, C, Robertson, M, Feskens, E, and Geleijnse, M
Published: 2023
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3. Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry

Author: de las Fuentes, L, Sung, YJ, Sitlani, CM, Avery, CL, Bartz, TM, Keyser, C de, Evans, DS, Li, X, Musani, SK, Ruiter, R, Smith, AV, Sun, F, Trompet, S, Xu, H, Arnett, DK, Bis, JC, Broeckel, U, Busch, EL, Chen, Y-DI, Correa, A, Cummings, SR, Floyd, JS, Ford, I, Guo, X, Harris, TB, Ikram, MA, Lange, L, Launer, LJ, Reiner, AP, Schwander, K, Smith, NL, Sotoodehnia, N, Stewart, JD, Stott, DJ, Stürmer, T, Taylor, KD, Uitterlinden, A, Vasan, RS, Wiggins, KL, Cupples, LA, Gudnason, V, Heckbert, SR, Jukema, JW, Liu, Y, Psaty, BM, Rao, DC, Rotter, JI, Stricker, B, Wilson, JG, and Whitsel, EA
Subjects: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Human Genome, Genetics, Cardiovascular, Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Black or African American, Diuretics, Genetic Variation, Genome-Wide Association Study, Humans, Hypertension, Lipids, White People, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract: Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p
Published: 2020

4. The Meta VCI Map consortium for meta‐analyses on strategic lesion locations for vascular cognitive impairment using lesion‐symptom mapping: Design and multicenter pilot study

Author: Weaver, Nick A, Zhao, Lei, Biesbroek, J Matthijs, Kuijf, Hugo J, Aben, Hugo P, Bae, Hee‐Joon, Caballero, Miguel ÁA, Chappell, Francesca M, Chen, Christopher PLH, Dichgans, Martin, Duering, Marco, Georgakis, Marios K, van der Giessen, Ruben S, Gyanwali, Bibek, Hamilton, Olivia KL, Hilal, Saima, Hofe, Elise M vom, de Kort, Paul LM, Koudstaal, Peter J, Lam, Bonnie YK, Lim, Jae‐Sung, Makin, Stephen DJ, Mok, Vincent CT, Shi, Lin, Hernández, Maria C Valdés, Venketasubramanian, Narayanaswamy, Wardlaw, Joanna M, Wollenweber, Frank A, Wong, Adrian, Xin, Xu, consortium, Meta VCI Map, DeCarli, C, Fletcher, EA, Maillard, P, Barnes, J, Sudre, CH, Schott, JM, Ikram, MA, Papma, JM, Steketee, RME, Vernooij, MW, Bordet, R, Lopes, R, Huang, C‐W, Frayne, R, McCreary, CR, Smith, EE, group, Calgary Normative Study, Backes, W, Köhler, S, van Oostenbrugge, RJ, Staals, J, Verhey, F, Cheng, CY, Kalaria, RN, Werring, D, Hsu, JL, Huang, K‐L, van der Grond, J, Jukema, JW, van der Mast, RC, Nijboer, TCW, group, Framingham Heart Study, Yu, K‐H, group, The Dutch Parelsnoer Institute–Neurodegenerative diseases, Schmidt, R, Pirpamer, L, MacIntosh, BJ, Robertson, AD, de Leeuw, F‐E, Tuladhar, AM, Chaturvedi, N, Tillin, T, Brodaty, H, Sachdev, P, group, TABASCO, Barkhof, F, van der Flier, WM, Kappelle, LJ, and Biessels, Geert Jan
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Biomedical Imaging, Atherosclerosis, Clinical Research, Brain Disorders, Acquired Cognitive Impairment, Stroke, Neurosciences, Meta VCI Map consortium, Cerebrovascular disease, Consortium, Data harmonization, Lesion location, Lesion-symptom mapping, Small vessel disease, Support vector regression, Vascular cognitive impairment, Genetics, Biological psychology
Abstract: IntroductionThe Meta VCI Map consortium performs meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping. Integration of data from different cohorts will increase sample sizes, to improve brain lesion coverage and support comprehensive lesion-symptom mapping studies.MethodsCohorts with available imaging on white matter hyperintensities or infarcts and cognitive testing were invited. We performed a pilot study to test the feasibility of multicenter data processing and analysis and determine the benefits to lesion coverage.ResultsForty-seven groups have joined Meta VCI Map (stroke n = 7800 patients; memory clinic n = 4900; population-based n = 14,400). The pilot study (six ischemic stroke cohorts, n = 878) demonstrated feasibility of multicenter data integration (computed tomography/magnetic resonance imaging) and achieved marked improvement of lesion coverage.DiscussionMeta VCI Map will provide new insights into the relevance of vascular lesion location for cognitive dysfunction. After the successful pilot study, further projects are being prepared. Other investigators are welcome to join.
Published: 2019

5. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author: Prins, Bram P, Mead, Timothy J, Brody, Jennifer A, Sveinbjornsson, Gardar, Ntalla, Ioanna, Bihlmeyer, Nathan A, van den Berg, Marten, Bork-Jensen, Jette, Cappellani, Stefania, Van Duijvenboden, Stefan, Klena, Nikolai T, Gabriel, George C, Liu, Xiaoqin, Gulec, Cagri, Grarup, Niels, Haessler, Jeffrey, Hall, Leanne M, Iorio, Annamaria, Isaacs, Aaron, Li-Gao, Ruifang, Lin, Honghuang, Liu, Ching-Ti, Lyytikäinen, Leo-Pekka, Marten, Jonathan, Mei, Hao, Müller-Nurasyid, Martina, Orini, Michele, Padmanabhan, Sandosh, Radmanesh, Farid, Ramirez, Julia, Robino, Antonietta, Schwartz, Molly, van Setten, Jessica, Smith, Albert V, Verweij, Niek, Warren, Helen R, Weiss, Stefan, Alonso, Alvaro, Arnar, David O, Bots, Michiel L, de Boer, Rudolf A, Dominiczak, Anna F, Eijgelsheim, Mark, Ellinor, Patrick T, Guo, Xiuqing, Felix, Stephan B, Harris, Tamara B, Hayward, Caroline, Heckbert, Susan R, Huang, Paul L, Jukema, JW, Kähönen, Mika, Kors, Jan A, Lambiase, Pier D, Launer, Lenore J, Li, Man, Linneberg, Allan, Nelson, Christopher P, Pedersen, Oluf, Perez, Marco, Peters, Annette, Polasek, Ozren, Psaty, Bruce M, Raitakari, Olli T, Rice, Kenneth M, Rotter, Jerome I, Sinner, Moritz F, Soliman, Elsayed Z, Spector, Tim D, Strauch, Konstantin, Thorsteinsdottir, Unnur, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Vaartjes, Ilonca, van der Meer, Peter, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wilson, James G, Xie, Zhijun, Asselbergs, Folkert W, Dörr, Marcus, van Duijn, Cornelia M, Gasparini, Paolo, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hansen, Torben, Kääb, Stefan, Kanters, Jørgen K, Kooperberg, Charles, Lehtimäki, Terho, Lin, Henry J, Lubitz, Steven A, Mook-Kanamori, Dennis O, Conti, Francesco J, Newton-Cheh, Christopher H, Rosand, Jonathan, Rudan, Igor, and Samani, Nilesh J
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, ADAMTS Proteins, Animals, Black People, Connexin 43, Electrocardiography, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mice, Middle Aged, Myocardium, Open Reading Frames, Polymorphism, Single Nucleotide, White People, Exome Sequencing, Exome chip, Conduction, ADAMTS6, Meta-analysis, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract: BackgroundGenome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.ResultsHere, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.ConclusionsOur approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
Published: 2018

6. Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

Author: Seyerle, AA, Sitlani, CM, Noordam, R, Gogarten, SM, Li, J, Li, X, Evans, DS, Sun, F, Laaksonen, MA, Isaacs, A, Kristiansson, K, Highland, HM, Stewart, JD, Harris, TB, Trompet, S, Bis, JC, Peloso, GM, Brody, JA, Broer, L, Busch, EL, Duan, Q, Stilp, AM, O'Donnell, CJ, Macfarlane, PW, Floyd, JS, Kors, JA, Lin, HJ, Li-Gao, R, Sofer, T, Méndez-Giráldez, R, Cummings, SR, Heckbert, SR, Hofman, A, Ford, I, Li, Y, Launer, LJ, Porthan, K, Newton-Cheh, C, Napier, MD, Kerr, KF, Reiner, AP, Rice, KM, Roach, J, Buckley, BM, Soliman, EZ, de Mutsert, R, Sotoodehnia, N, Uitterlinden, AG, North, KE, Lee, CR, Gudnason, V, Stürmer, T, Rosendaal, FR, Taylor, KD, Wiggins, KL, Wilson, JG, Chen, Y-DI, Kaplan, RC, Wilhelmsen, K, Cupples, LA, Salomaa, V, van Duijn, C, Jukema, JW, Liu, Y, Mook-Kanamori, DO, Lange, LA, Vasan, RS, Smith, AV, Stricker, BH, Laurie, CC, Rotter, JI, Whitsel, EA, Psaty, BM, and Avery, CL
Subjects: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Genetics, Cardiovascular, Human Genome, Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Electrocardiography, Ethnicity, Female, Genomics, Heart Rate, Humans, Longitudinal Studies, Male, Middle Aged, Pharmacogenetics, Polymorphism, Single Nucleotide, Sodium Chloride Symporter Inhibitors, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract: Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P
Published: 2018

7. Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group

Author: Floyd, JS, Sitlani, CM, Avery, CL, Noordam, R, Li, X, Smith, AV, Gogarten, SM, Li, J, Broer, L, Evans, DS, Trompet, S, Brody, JA, Stewart, JD, Eicher, JD, Seyerle, AA, Roach, J, Lange, LA, Lin, HJ, Kors, JA, Harris, TB, Li-Gao, R, Sattar, N, Cummings, SR, Wiggins, KL, Napier, MD, Stürmer, T, Bis, JC, Kerr, KF, Uitterlinden, AG, Taylor, KD, Stott, DJ, de Mutsert, R, Launer, LJ, Busch, EL, Méndez-Giráldez, R, Sotoodehnia, N, Soliman, EZ, Li, Y, Duan, Q, Rosendaal, FR, Slagboom, PE, Wilhelmsen, KC, Reiner, AP, Chen, Y-DI, Heckbert, SR, Kaplan, RC, Rice, KM, Jukema, JW, Johnson, AD, Liu, Y, Mook-Kanamori, DO, Gudnason, V, Wilson, JG, Rotter, JI, Laurie, CC, Psaty, BM, Whitsel, EA, Cupples, LA, and Stricker, BH
Subjects: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Genetics, Cardiovascular, Human Genome, Heart Disease, Patient Safety, Clinical Research, Good Health and Well Being, Aged, Cardiovascular Diseases, Cytochrome P-450 CYP2C9, Diabetes Mellitus, Type 2, Drug-Related Side Effects and Adverse Reactions, Electrocardiography, Ethnicity, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Pharmacogenetics, Pharmacogenomic Testing, Sulfonylurea Compounds, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract: Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P
Published: 2018

8. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author: Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, Liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffmann, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewart, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, deJager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, Y-C, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nöthen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, and Chasman, DI
Subjects: Biological Psychology, Clinical and Health Psychology, Psychology, Human Genome, Neurosciences, Genetics, Clinical Research, Aging, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Cell Adhesion Molecules, Cognition, Cohort Studies, Executive Function, Female, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genomics, Humans, Introns, Male, Middle Aged, Neuropsychological Tests, Polymorphism, Single Nucleotide, White People, gamma-Aminobutyric Acid, Generation Scotland, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
Published: 2016

9. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Author: Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Generation Scotland, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, and Wright, AF
Subjects: Generation Scotland, Humans, Genetic Predisposition to Disease, HMGN1 Protein, Cohort Studies, Cognition, Cognition Disorders, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Scotland, Female, Male, Atherosclerosis, Genome-Wide Association Study, and over, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
Published: 2015

10. Drug–gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval

Author: Avery, CL, Sitlani, CM, Arking, DE, Arnett, DK, Bis, JC, Boerwinkle, E, Buckley, BM, Ida Chen, Y-D, de Craen, AJM, Eijgelsheim, M, Enquobahrie, D, Evans, DS, Ford, I, Garcia, ME, Gudnason, V, Harris, TB, Heckbert, SR, Hochner, H, Hofman, A, Hsueh, W-C, Isaacs, A, Jukema, JW, Knekt, P, Kors, JA, Krijthe, BP, Kristiansson, K, Laaksonen, M, Liu, Y, Li, X, MacFarlane, PW, Newton-Cheh, C, Nieminen, MS, Oostra, BA, Peloso, GM, Porthan, K, Rice, K, Rivadeneira, FF, Rotter, JI, Salomaa, V, Sattar, N, Siscovick, DS, Slagboom, PE, Smith, AV, Sotoodehnia, N, Stott, DJ, Stricker, BH, Stürmer, T, Trompet, S, Uitterlinden, AG, van Duijn, C, Westendorp, RGJ, Witteman, JC, Whitsel, EA, and Psaty, BM
Subjects: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Genetics, Biotechnology, Human Genome, Patient Safety, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Computer Simulation, Cross-Sectional Studies, Drug-Related Side Effects and Adverse Reactions, Electrocardiography, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Linear Models, Long QT Syndrome, Markov Chains, Pharmacogenetics, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, White People, gene-environment interaction, genetic epidemiology, QT interval, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract: Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
Published: 2014

11. Stroke genetics informs drug discovery and risk prediction across ancestries

Author: Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, Gravel, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, and Gravel, S
Abstract: Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Published: 2022

12. A saturated map of common genetic variants associated with human height

Author: Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, Hirschhorn, JN, Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, and Hirschhorn, JN
Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Published: 2022

13. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Author: Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, Raikkonen, K, Lahti, J, Tuominen, S, Yang, Q, Pergola, G, Ahmad, S, Amin, N, Armstrong, NJ, Beiser, A, Bey, K, Bis, JC, Boerwinkle, E, Bressler, J, Campbell, A, Campbell, H, Chen, Q, Corley, J, Cox, SR, Davies, G, De Jager, PL, Derks, EM, Faul, JD, Fitzpatrick, AL, Fohner, AE, Ford, I, Fornage, M, Gerring, Z, Grabe, HJ, Grodstein, F, Gudnason, V, Simonsick, E, Holliday, EG, Joshi, PK, Kajantie, E, Kaprio, J, Karell, P, Kleineidam, L, Knol, MJ, Kochan, NA, Kwok, JB, Leber, M, Lam, M, Lee, T, Li, S, Loukola, A, Luck, T, Marioni, RE, Mather, KA, Medland, S, Mirza, SS, Nalls, MA, Nho, K, O'Donnell, A, Oldmeadow, C, Painter, J, Pattie, A, Reppermund, S, Risacher, SL, Rose, RJ, Sadashivaiah, V, Scholz, M, Satizabal, CL, Schofield, PW, Schraut, KE, Scott, RJ, Simino, J, Smith, AV, Smith, JA, Stott, DJ, Surakka, I, Teumer, A, Thalamuthu, A, Trompet, S, Turner, ST, van der Lee, SJ, Villringer, A, Voelker, U, Wilson, RS, Wittfeld, K, Vuoksimaa, E, Xia, R, Yaffe, K, Yu, L, Zare, H, Zhao, W, Ames, D, Attia, J, Bennett, DA, Brodaty, H, Chasman, DI, Goldman, AL, Hayward, C, Ikram, MA, Jukema, JW, Kardia, SLR, Lencz, T, Loeffler, M, Mattay, VS, Palotie, A, Psaty, BM, Ramirez, A, Ridker, PM, Riedel-Heller, SG, Sachdev, PS, Saykin, AJ, Scherer, M, Schofield, PR, Sidney, S, Starr, JM, Trollor, J, Ulrich, W, Wagner, M, Weir, DR, Wilson, JF, Wright, MJ, Weinberger, DR, Debette, S, Eriksson, JG, Mosley, TH, Launer, LJ, van Duijn, CM, Deary, IJ, Seshadri, S, and Raikkonen, K
Abstract: Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
Published: 2022

14. Stroke genetics informs drug discovery and risk prediction across ancestries (vol 611, pg 115, 2022)

Author: Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, and Debette, S
Published: 2022

15. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author: Temprano-Sagrera, G, Sitlani, CM, Bone, WP, Martin-Bornez, M, Voight, BF, Morrison, AC, Damrauer, SM, de Vries, PS, Smith, NL, Sabater-Lleal, M, Krupinksi, J, Dehghan, A, Heath, AS, Reiner, AP, Johnson, A, Richmond, A, Peters, A, van Hylckama Vlieg, A, McKnight, B, Psaty, BM, Hayward, C, Ward-Caviness, C, O’Donnell, C, Chasman, D, Strachan, DP, Tregouet, DA, Mook-Kanamori, D, Gill, D, Thibord, F, Asselbergs, FW, Leebeek, FWG, Rosendaal, FR, Davies, G, Homuth, G, Temprano, G, Campbell, H, Taylor, HA, Bressler, J, Huffman, JE, Rotter, JI, Yao, J, Wilson, JF, Bis, JC, Hahn, JM, Desch, KC, Wiggins, KL, Raffield, LM, Bielak, LF, Yanek, LR, Kleber, ME, Mueller, M, Kavousi, M, Mangino, M, Liu, M, Brown, MR, Conomos, MP, Jhun, MA, Chen, MH, de Maat, MPM, Pankratz, N, Peyser, PA, Elliot, P, Wei, P, Wild, PS, Morange, PE, van der Harst, P, Yang, Q, Le, NQ, Marioni, R, Li, R, Cox, SR, Trompet, S, Felix, SB, Völker, U, Tang, W, Koenig, W, Jukema, JW, Guo, X, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, de Andrade, M, Brody, JA, Pattee, JW, Haessler, J, Brumpton, BM, Chasman, DI, Suchon, P, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Temprano-Sagrera, G, Sitlani, CM, Bone, WP, Martin-Bornez, M, Voight, BF, Morrison, AC, Damrauer, SM, de Vries, PS, Smith, NL, Sabater-Lleal, M, Krupinksi, J, Dehghan, A, Heath, AS, Reiner, AP, Johnson, A, Richmond, A, Peters, A, van Hylckama Vlieg, A, McKnight, B, Psaty, BM, Hayward, C, Ward-Caviness, C, O’Donnell, C, Chasman, D, Strachan, DP, Tregouet, DA, Mook-Kanamori, D, Gill, D, Thibord, F, Asselbergs, FW, Leebeek, FWG, Rosendaal, FR, Davies, G, Homuth, G, Temprano, G, Campbell, H, Taylor, HA, Bressler, J, Huffman, JE, Rotter, JI, Yao, J, Wilson, JF, Bis, JC, Hahn, JM, Desch, KC, Wiggins, KL, Raffield, LM, Bielak, LF, Yanek, LR, Kleber, ME, Mueller, M, Kavousi, M, Mangino, M, Liu, M, Brown, MR, Conomos, MP, Jhun, MA, Chen, MH, de Maat, MPM, Pankratz, N, Peyser, PA, Elliot, P, Wei, P, Wild, PS, Morange, PE, van der Harst, P, Yang, Q, Le, NQ, Marioni, R, Li, R, Cox, SR, Trompet, S, Felix, SB, Völker, U, Tang, W, Koenig, W, Jukema, JW, Guo, X, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, de Andrade, M, Brody, JA, Pattee, JW, Haessler, J, Brumpton, BM, Chasman, DI, Suchon, P, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, and Armasu, SM
Abstract: Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Published: 2022

16. Subclinical thyroid dysfunction and incident diabetes: a systematic review and an individual participant data analysis of prospective cohort studies

Author: Alwan H, Villoz F, Feller M, Dullaart RPF, Bakker SJL, Peeters RP, Kavousi M, Bauer DC, Cappola AR, Yeap BB, Walsh JP, Brown SJ, Ceresini G, Ferrucci L, Gussekloo J, Trompet S, Iacoviello M, Moon JH, Razvi S, Bensenor IM, Azizi F, Amouzegar A, Valdés S, Colomo N, Wareham NJ, Jukema JW, Westendorp RGJ, Kim KW, Rodondi N, Giovane CD
Published: 2022
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17. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus (vol 13, 1222, 2022)

Author: Stacey, D, Chen, LY, Stanczyk, PJ, Howson, JMM, Mason, AM, Burgess, S, MacDonald, S, Langdown, J, McKinney, H, Downes, K, Farahi, N, Peters, JE, Basu, S, Pankow, JS, Tang, WH, Pankratz, N, Sabater-Lleal, M, de Vries, PS, Smith, NL, Dehghan, A, Heath, AS, Morrison, AC, Reiner, AP, Johnson, A, Richmond, A, Peters, A, Vlieg, AV, McKnight, B, Psaty, BM, Hayward, C, Ward-Caviness, C, O'Donnell, C, Chasman, D, Strachan, DP, Tregouet, DA, Mook-Kanamori, D, Gill, D, Thibord, F, Asselbergs, FW, Leebeek, FWG, Rosendaal, FR, Davies, G, Homuth, G, Temprano, G, Campbell, H, Taylor, HA, Bressler, J, Huffman, JE, Rotter, JI, Yao, J, Wilson, JF, Bis, JC, Hahn, JM, Desch, KC, Wiggins, KL, Raffield, LM, Bielak, LF, Yanek, LR, Kleber, ME, Mueller, M, Kavousi, M, Mangino, M, Conomos, MP, Liu, ML, Brown, MR, Jhun, MA, Chen, MH, de Maat, MPM, Peyser, PA, Elliot, P, Wei, P, Wild, PS, Morange, PE, van der Harst, P, Yang, Q, Le, NQ, Marioni, R, Li, RF, Damrauer, SM, Cox, SR, Trompet, S, Felix, SB, Volker, U, Koenig, W, Jukema, JW, Guo, XQ, Gelinas, AD, Schneider, DJ, Janjic, N, Samani, NJ, Ye, S, Summers, C, Chilvers, ER, Danesh, J, and Paul, DS
Published: 2022

18. Publisher Correction:Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author: Surendran, P, Feofanova, EV, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, AV, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Velez Edwards, DR, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, De Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, I, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, YV, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, AI, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Davey Smith, G, Boer, RAD, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, MI, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, JI, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, Van der Harst, P, Van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, DI, Levy, D, Newton-Cheh, C, Munroe, PB, Howson, JMM, and United Kingdom Research and Innovation
Subjects: Genetics & Heredity, Understanding Society Scientific Group, Science & Technology, business.industry, Published Erratum, Million Veteran Program, MEDLINE, Computational biology, 06 Biological Sciences, Biology, Blood pressure, Text mining, Meta-analysis, EPIC-InterAct, Genetics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business, Life Sciences & Biomedicine, EPIC-CVD, 11 Medical and Health Sciences, LifeLines Cohort Study, Developmental Biology
Abstract: In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article.
Published: 2021

19. Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Author: Ahluwalia, TS, Prins, BP, Abdollahi, M, Armstrong, NJ, Aslibekyan, S, Bain, L, Jefferis, B, Baumert, J, Beekman, M, Ben-Shlomo, Y, Bis, JC, Mitchell, BD, de Geus, E, Delgado, GE, Marek, D, Eriksson, J, Kajantie, E, Kanoni, S, Kemp, JP, Lu, C, Marioni, RE, McLachlan, S, Milaneschi, Y, Nolte, IM, Petrelis, AM, Porcu, E, Sabater-Lleal, M, Naderi, E, Seppälä, I, Shah, T, Singhal, G, Standl, M, Teumer, A, Thalamuthu, A, Thiering, E, Trompet, S, Ballantyne, CM, Benjamin, EJ, Casas, JP, Toben, C, Dedoussis, G, Deelen, J, Durda, P, Engmann, J, Feitosa, MF, Grallert, H, Hammarstedt, A, Harris, SE, Homuth, G, Hottenga, J-J, Jalkanen, S, Jamshidi, Y, Jawahar, MC, Jess, T, Kivimaki, M, Kleber, ME, Lahti, J, Liu, Y, Marques-Vidal, P, Mellström, D, Mooijaart, SP, Müller-Nurasyid, M, Penninx, B, Revez, JA, Rossing, P, Räikkönen, K, Sattar, N, Scharnagl, H, Sennblad, B, Silveira, A, Pourcain, BS, Timpson, NJ, Trollor, J, CHARGE Inflammation Working Group, van Dongen, J, Van Heemst, D, Visvikis-Siest, S, Vollenweider, P, Völker, U, Waldenberger, M, Willemsen, G, Zabaneh, D, Morris, RW, Arnett, DK, Baune, BT, Boomsma, DI, Chang, Y-PC, Deary, IJ, Deloukas, P, Eriksson, JG, Evans, DM, Ferreira, MA, Gaunt, T, Gudnason, V, Hamsten, A, Heinrich, J, Hingorani, A, Humphries, SE, Jukema, JW, Koeing, W, Kumari, M, Kutalik, Z, Lawlor, DA, Lehtimäki, T, März, W, Mather, K, Naitza, S, Nauck, M, Ohlsson, C, Price, JF, Raitakari, O, Rice, K, Sachdev, PS, Slagboom, E, Sørensen, TIA, Spector, T, Stacey, D, Stathopoulou, MG, Tanaka, T, Wannamethee, SG, Whincup, P, Rotter, JI, Dehghan, A, Boerwinkle, E, Psaty, BM, Snieder, H, and Alizadeh, BZ
Abstract: Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Published: 2021

20. Associations of Cytomegalovirus Infection With All-Cause and Cardiovascular Mortality in Multiple Observational Cohort Studies of Older Adults

Author: Chen, S, Pawelec, G, Trompet, S, Goldeck, D, Mortensen, LH, Slagboom, PE, Christensen, K, Gussekloo, J, Kearney, P, Buckley, BM, Ford, I, Jukema, JW, Westendorp, RGJ, Maier, AB, Chen, S, Pawelec, G, Trompet, S, Goldeck, D, Mortensen, LH, Slagboom, PE, Christensen, K, Gussekloo, J, Kearney, P, Buckley, BM, Ford, I, Jukema, JW, Westendorp, RGJ, and Maier, AB
Abstract: BACKGROUND: Whether latent cytomegalovirus (CMV) infection in older adults has any substantial health consequences is unclear. Here, we sought associations between CMV-seropositivity and IgG titer with all-cause and cardiovascular mortality in 5 longitudinal cohorts. METHODS: Leiden Longevity Study, Prospective Study of Pravastatin in the Elderly at Risk, Longitudinal Study of Aging Danish Twins, and Leiden 85-plus Study were assessed at median (2.8-11.4 years) follow-up . Cox regression and random effects meta-analysis were used to estimate mortality risk dependent on CMV serostatus and/or IgG antibody titer, in quartiles after adjusting for confounders. RESULTS: CMV-seropositivity was seen in 47%-79% of 10 122 white community-dwelling adults aged 59-93 years. Of these, 3519 had died on follow-up (579 from cardiovascular disease). CMV seropositivity was not associated with all-cause (hazard ratio [HR], 1.05; 95% confidence interval [CI], .97-1.14) or cardiovascular mortality (HR, 0.97; 95% CI, .83-1.13). Subjects in the highest CMV IgG quartile group had increased all-cause mortality relative to CMV-seronegatives (HR, 1.16; 95% CI, 1.04-1.29) but this association lost significance after adjustment for confounders (HR, 1.13; 95% CI, .99-1.29). The lack of increased mortality risk was confirmed in subanalyses. CONCLUSIONS: CMV infection is not associated with all-cause or cardiovascular mortality in white community-dwelling older adults.
Published: 2021

21. Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses

Author: Bos, Maxime, Goulding, NJ, Lee, MA, Hofman, Bert, Bot, M, Pool, R, Vijfhuizen, LS, Zhang, K, Li, CH, Mustafa, R, Neville, MJ, Li-Gao, R, Trompet, S, Beekman, M, Biermasz, NR, Boomsma, DI, Boer, I, Christodoulides, C, Dehghan, A, van Dijk, KW, Ford, I, Ghanbari, Mohsen, Heijmans, BT, Ikram, Arfan, Jukema, JW, Mook, Dennis, Karpe, F, Luik, Annemarie, Lumey, LH, van den Maagdenberg, A, Mooijaart, SP, de Mutsert, R, Penninx, B, Rensen, PCN, Richmond, Rebecca, Rosendaal, FR, Sattar, N, Schoevers, RA, Slagboom, PE, Terwindt, GM, Thesing, CS, Wade, KH, Wijsman, CA, Willemsen, G, Zwinderman, AH, van Heemst, D, Noordam, R, Lawlor, DA, Bos, Maxime, Goulding, NJ, Lee, MA, Hofman, Bert, Bot, M, Pool, R, Vijfhuizen, LS, Zhang, K, Li, CH, Mustafa, R, Neville, MJ, Li-Gao, R, Trompet, S, Beekman, M, Biermasz, NR, Boomsma, DI, Boer, I, Christodoulides, C, Dehghan, A, van Dijk, KW, Ford, I, Ghanbari, Mohsen, Heijmans, BT, Ikram, Arfan, Jukema, JW, Mook, Dennis, Karpe, F, Luik, Annemarie, Lumey, LH, van den Maagdenberg, A, Mooijaart, SP, de Mutsert, R, Penninx, B, Rensen, PCN, Richmond, Rebecca, Rosendaal, FR, Sattar, N, Schoevers, RA, Slagboom, PE, Terwindt, GM, Thesing, CS, Wade, KH, Wijsman, CA, Willemsen, G, Zwinderman, AH, van Heemst, D, Noordam, R, and Lawlor, DA
Abstract: Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.
Published: 2021

22. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Lagou, V, Mägi, R, Hottenga, JJ, Grallert, H, Perry, JR, Bouatia-Naji, N, Marullo, L, Rybin, D, Jansen, R, Min, JL, Dimas, AS, Ulrich, A, Zudina, L, Gådin, JR, Jiang, L, Faggian, A, Bonnefond, A, Fadista, J, Stathopoulou, MG, Isaacs, Aaron, Willems, SM, Navarro, P, Tanaka, T, Jackson, AU, Montasser, ME, O’Connell, JR, Bielak, LF, Webster, RJ, Saxena, R, Stafford, JM, Pourcain, BS, Timpson, NJ, Salo, P, Shin, SY, Amin, Najaf, Smith, AV, Li, G, Verweij, N, Goel, A, Ford, I, Johnson, PCD, Johnson, T, Kapur, K, Thorleifsson, G, Strawbridge, RJ, Rasmussen-Torvik, LJ, Esko, T, Mihailov, E, Fall, T, Fraser, RM, Mahajan, A, Kanoni, S, Giedraitis, V, Kleber, ME, Silbernagel, G, Meyer, J, Müller-Nurasyid, M, Ganna, A, Sarin, AP, Yengo, L, Shungin, D, Luan, J, Horikoshi, M, An, P, Sanna, S, Boettcher, Y, Rayner, NW, Nolte, IM, Zemunik, T, van Iperen, E, Kovacs, P, Hastie, ND, Wild, SH, McLachlan, S, Campbell, S, Polasek, O, Carlson, O, Egan, J, Kiess, W, Willemsen, G, Kuusisto, J, Laakso, M, Dimitriou, M, Hicks, AA, Rauramaa, R, Bandinelli, S, Thorand, B, Liu, Y, Miljkovic, I, Lind, L, Doney, A, Perola, M, Hingorani, A, Kivimaki, M, Kumari, M, Bennett, AJ, Groves, CJ, Herder, C, Koistinen, HA, Kinnunen, L, de Faire, U, Bakker, SJ, Uusitupa, M, Palmer, CN, Jukema, JW, Sattar, N, Pouta, A, Snieder, H, Boerwinkle, E, Pankow, JS, Magnusson, PKE, Krus, U, Scapoli, C, de Geus, EJCN, Blüher, M, Wolffenbuttel, BH, Province, MA, Abecasis, GR, Meigs, JB, Hovingh, GK, Lindström, J, Wilson, JF, Wright, AF, Dedoussis, GVZ, Bornstein, SR, Schwarz, PEH, Tönjes, A, Winkelmann, BR, Boehm, BO, März, W, Metspalu, A, Price, JF, Deloukas, P, Körner, A, Lakka, TA, Keinanen-Kiukaanniemi, SM, Saaristo, TE, Bergman, RN, Tuomilehto, J, Wareham, NJ, Langenberg, C, Männistö, S, Franks, PW, Hayward, C, Vitart, V, Kaprio, J, Visvikis-Siest, S, Balkau, B, Altshuler, D, Rudan, I, Stumvoll, M, Campbell, H, Duijn, Cornelia, Gieger, C, Illig, T, Ferrucci, L, Pedersen, NL, Pramstaller, PP, Boehnke, M, Frayling, TM, Shuldiner, AR, Peyser, PA, Kardia, SL, Palmer, LJ, Penninx, BWJH, Meneton, P, Harris, TB, Navis, G, van der Harst, P, Smith, GD, Forouhi, NG, Loos, RJ, Salomaa, V, Soranzo, N, Boomsma, DI, Groop, L, Tuomi, T, Hofman, Bert, Munroe, PB, Gudnason, V, Siscovick, DS, Watkins, H, Lecoeur, C, Vollenweider, P, Franco-Cereceda, A, Eriksson, P, Jarvelin, M R R, Stefansson, K, Hamsten, A, Nicholson, G, Karpe, F, Dermitzakis, ET, Lindgren, CM, McCarthy, MI, Froguel, P, Kaakinen, MA, Lyssenko, V, Watanabe, RM, Ingelsson, E, Florez, JC, Dupuis, J, Barroso, I, Morris, AP, Prokopenko, I, Lagou, V, Mägi, R, Hottenga, JJ, Grallert, H, Perry, JR, Bouatia-Naji, N, Marullo, L, Rybin, D, Jansen, R, Min, JL, Dimas, AS, Ulrich, A, Zudina, L, Gådin, JR, Jiang, L, Faggian, A, Bonnefond, A, Fadista, J, Stathopoulou, MG, Isaacs, Aaron, Willems, SM, Navarro, P, Tanaka, T, Jackson, AU, Montasser, ME, O’Connell, JR, Bielak, LF, Webster, RJ, Saxena, R, Stafford, JM, Pourcain, BS, Timpson, NJ, Salo, P, Shin, SY, Amin, Najaf, Smith, AV, Li, G, Verweij, N, Goel, A, Ford, I, Johnson, PCD, Johnson, T, Kapur, K, Thorleifsson, G, Strawbridge, RJ, Rasmussen-Torvik, LJ, Esko, T, Mihailov, E, Fall, T, Fraser, RM, Mahajan, A, Kanoni, S, Giedraitis, V, Kleber, ME, Silbernagel, G, Meyer, J, Müller-Nurasyid, M, Ganna, A, Sarin, AP, Yengo, L, Shungin, D, Luan, J, Horikoshi, M, An, P, Sanna, S, Boettcher, Y, Rayner, NW, Nolte, IM, Zemunik, T, van Iperen, E, Kovacs, P, Hastie, ND, Wild, SH, McLachlan, S, Campbell, S, Polasek, O, Carlson, O, Egan, J, Kiess, W, Willemsen, G, Kuusisto, J, Laakso, M, Dimitriou, M, Hicks, AA, Rauramaa, R, Bandinelli, S, Thorand, B, Liu, Y, Miljkovic, I, Lind, L, Doney, A, Perola, M, Hingorani, A, Kivimaki, M, Kumari, M, Bennett, AJ, Groves, CJ, Herder, C, Koistinen, HA, Kinnunen, L, de Faire, U, Bakker, SJ, Uusitupa, M, Palmer, CN, Jukema, JW, Sattar, N, Pouta, A, Snieder, H, Boerwinkle, E, Pankow, JS, Magnusson, PKE, Krus, U, Scapoli, C, de Geus, EJCN, Blüher, M, Wolffenbuttel, BH, Province, MA, Abecasis, GR, Meigs, JB, Hovingh, GK, Lindström, J, Wilson, JF, Wright, AF, Dedoussis, GVZ, Bornstein, SR, Schwarz, PEH, Tönjes, A, Winkelmann, BR, Boehm, BO, März, W, Metspalu, A, Price, JF, Deloukas, P, Körner, A, Lakka, TA, Keinanen-Kiukaanniemi, SM, Saaristo, TE, Bergman, RN, Tuomilehto, J, Wareham, NJ, Langenberg, C, Männistö, S, Franks, PW, Hayward, C, Vitart, V, Kaprio, J, Visvikis-Siest, S, Balkau, B, Altshuler, D, Rudan, I, Stumvoll, M, Campbell, H, Duijn, Cornelia, Gieger, C, Illig, T, Ferrucci, L, Pedersen, NL, Pramstaller, PP, Boehnke, M, Frayling, TM, Shuldiner, AR, Peyser, PA, Kardia, SL, Palmer, LJ, Penninx, BWJH, Meneton, P, Harris, TB, Navis, G, van der Harst, P, Smith, GD, Forouhi, NG, Loos, RJ, Salomaa, V, Soranzo, N, Boomsma, DI, Groop, L, Tuomi, T, Hofman, Bert, Munroe, PB, Gudnason, V, Siscovick, DS, Watkins, H, Lecoeur, C, Vollenweider, P, Franco-Cereceda, A, Eriksson, P, Jarvelin, M R R, Stefansson, K, Hamsten, A, Nicholson, G, Karpe, F, Dermitzakis, ET, Lindgren, CM, McCarthy, MI, Froguel, P, Kaakinen, MA, Lyssenko, V, Watanabe, RM, Ingelsson, E, Florez, JC, Dupuis, J, Barroso, I, Morris, AP, and Prokopenko, I
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Published: 2021

23. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

Author: Lincoff, A. Michael, Nicholls, Stephen J., Riesmeyer, Jeffrey S., Barter, Philip J., Brewer, H. Bryan, Fox, Keith A. A., Gibson, C. Michael, Granger, Christopher, Menon, Venu, Montalescot, Gilles, Rader, Daniel, Tall, Alan R., McErlean, Ellen, Wolski, Kathy, Ruotolo, Giacomo, Vangerow, Burkhard, Weerakkody, Govinda, Goodman, Shaun G., Conde, Diego, McGuire, Darren K., Nicolau, Jose C., Leiva-Pons, Jose L., Pesant, Yves, Li, Weimin, Kandath, David, Kouz, Simon, Tahirkheli, Naeem, Mason, Denise, Nissen, Steven E. Del Valle M, Finnell JB, Standley J, Poi K, Croaning J, Tong YC, Guerra JL, Guasparini G, Hubert C, Ardissino D, Betteridge J, Borghi C, Bruckert E, Chiang CE, Cinteza M, Dalby AJ, Erlinge D, Fernandez-Ortiz A, Ge J, Gottlieb S, Goudev A, Gratsiansky N, Huber K, Ilavská A, Jeong MH, Jukema JW, Katus H, Keltai M, Krum H, Nielsen H, Ogawa H, Ongen Z, Parkhomenko A, Raugaliene R, Renkin J, Rynkiewicz A, Steinhubl S, White H, Widimsky P, Zhu J, Armstrong P, Ridker P, Mahaffey K, Steg G, Wittes J, Bhargava A, Chenier M, Coleman C, Cremer P, Jellis C, Lahoud R, Lappe J, Min D, Monteleone P, Newton D, Stegman B, Senn T, Katzan I, Sharma J, Uchino K, Vora N, Brown K, Fabec D, Piper P, Preston S, Colombo T, Pagel-Langenickel I, Penev P, Maixing A, Crowley K, Sarkar S, Torosyan N, Castano L, Tran D, Dena V, Blain L, Keenan G, Slade K, Quinlan E, Edwards R, Ren H, Glenny J, Maffei L, Albisu Di Gennaro J, Caccavo A, Prado A, Colombo H, Luquez H, Lobo Marquez L, Hammett C, Blombery P, Colquhoun D, Amerena J, Howes L, Cooke D, Simpson R, Horowitz J, Sullivan D, Proietto J, Yeo W, Hirschl M, Hanusch U, Drexel H, Brodmann M, Wollaert B, De Wolf L, Delforge M, Vanwelden J, Peeters A, Siqueira Bodart J, Montenegro R, Franken M, Eliaschewitz F, Parvanova Z, Raev D, Mincheva V, Kichukov K, Stoyanov M, Apostolova E, Tzekova M, Dimov B, Lazov P, Devedzhiev T, Dion D, Poirier P, Lavoie JP, Lonn E, Shukla D, Chehayeb R, Nault P, Gaudet D, Tardif JC, Beaudry Y, Bakbak A, Wong B, St-Maurice F, Labonte R, Polasek P, Sweet M, Bhargava R, Nawaz S, Pandey S, Tishler S, Peterson S, O’Keefe D, Genest J, Syan R, Leiter L, Li H, Ma W, Ma C, Xu D, Li X, Hala T, Machova V, Smejkalova O, Vodnansky P, Reichert P, Velimsky T, Matuska J, Machkova M, Jerabek O, Kuchar J, Rasmussen T, Lindgren L, Alexandersen P, Bang L, Brønnum-Schou J, Valter I, Soots M, Lanno R, Rosenthal S, Cottin Y, Elbaz M, Lafitte S, Silvain J, Coste P, Rangé G, Gosse P, Morel O, Berrouschot J, Bourhaial H, Toursarkissian N, Appel KF, Rieker W, Stellbrink C, Münzel T, Geisler T, Kadel C, Giannitsis E, Trenk D, vom Dahl J, Dorsel T, Singer O, Schäufele T, Natour M, Ozaki R, Lau E, Chan K, Yeung V, Yu C, Lakatos F, Zólyomi S, Vangel S, Merkely B, Szakal I, Sipos A, Laszloczky A, Kis E, Szocs A, Szántai G, Faludi P, Kancz S, Oroszlan T, Hamoud S, Francis A, Chorin E, Leibowitz D, Kracoff O, Weisz G, Schiff E, Bitzur R, Hussein O, Di Lorenzo L, Visona A, Mos L, De Luca G, Salvioni A, Rubba P, Imberti D, Bucci M, Saku K, Sueyoshi A, Ohshima K, Kazatani Y, Shimizu M, Fujii K, Higa N, Kawamitsu K, Shimomura H, Hoshizaki H, Tashiro H, Baden M, Ueda O, Tanabe J, Momiyama Y, Hosokawa S, Takahashi N, Kimura K, Fujinaga H, Masutani M, Kuramochi T, Higashikata T, Ichikawa S, Yamagishi M, Sakota S, Sakuragi S, Suzuki M, Taguchi S, Nakamura T, Ozaki Y, Tsujita K, Yasuda S, Ando K, Fujimoto K, Tanabe K, Fukunaga M, Kavaliauskiene R, Motiejuniene L, Slapikas R, Jarasuniene D, De los Rios Ibarra M, Alcocer Gamba M, Nevarez Ruiz L, Fajardo-Campos P, Llamas Esperon G, Violante Ortiz R, Stobschinski de Alba C, Guizar Sanchez C, Guerra Lopez A, Montano E, Miracle S, Fanghanel G, Lenderink T, Troquay R, Van Leendert R, van Eck J, Hamer B, Ronner E, Karalis I, Lok D, Magro M, Westendorp I, Stroes E, De Melker E, Verhave G, Plomp J, Bronzwaer P, Wiersma J, Kooy A, Herrman JP, Imholz B, de Groot M, Devlin G, Elliott J, Benatar J, Harding S, Hart H, Young C, Mirek-Bryniarska E, Gniot J, Broncel M, Kozina M, Kus W, Sciborski R, Lesnik J, Kawka-Urbanek T, Krzyzanowski M, Okopien B, Wierzbicka K, Dyczek A, Ochean V, Copaci I, Matei C, Pruna C, Constantinescu M, Minescu B, Stamate C, Boldueva S, Markov V, Alexeeva N, Chizhov P, Supryadkina T, Petrochenkova N, Zrazhevsky K, Barbarash O, Gurevich V, Hranai M, Gergel V, Dzupina A, Uhliar R, Vinanska D, Fazekas F, Bugan W, Saaiman J, Nortje H, Theron H, Bernhardi D, Ramlachan P, Van-Zyl L, Basson M, Venter T, Kim D, Han S, Park G, Hwang K, Rhee M, Cho B, Jeong J, Hong B, Chang K, Garcia Puig J, Fuentes Jiménez F, Nieto Iglesias LJ, Pintó Sala X, Gamez JM, Sánchez Álvarez J, Hernandez García JM, Olsson A, Mooe T, Tengmark BO, Lindholm CJ, Hansen O, Tyden P, Moccetti T, Binder R, Ueng K, Lai W, Shyu K, Hsieh I, Sheu W, Chen J, Altunkeser B, Erkan A, Karpenko O, Kaydashev I, Yagensky A, Kovalenko V, Brunskill J, Barr C, Cecil J, Cahill T, A Gorog D, Bakhai A, Coulson W, Gorog D, Loftus I, Haddad T, Hotchkiss D, Isserman S, Janik M, Weinstein D, Wilson S, Butman S, Hearne S, Khan F, Nadar V, Zelman R, Benton R, Flores E, Kahn B, Soni A, Asbill B, Singal D, Dy J, Foucauld J, Crenshaw B, Rogers W, Aslam A, Lieber I, Shah P, Durr S, Spencer R, Mahal S, Cheng S, Abadier R, Gilmore R, Staniloae C, Miller G, Seals A, Jetty P, Mathis C, Henry S, Murray A, Felten W, Navas J, Gudipati R, Singh N, West S, Sabatino K, Crater T, Amin J, Dosh K, Earl J, Z Jafar M, Gelernt M, Kutner M, Salazar J, Krantzler J, El-Ahdab F, Lader E, Zakhary B, Miller S, Madder R, Khan T, Khan M, Collis W, Evans J, Prodafikas J, Panchal V, Cohen K, Weiss R, Dietrich D, Vogel C, Mascarenhas V, Seaworth J, Teklinski A, Davalos J, Dehning M, Herzog W, Snyder H, Talano J, Donahoe S, Hunter J, Sandoval J, Batchelor W, Brautigam D, Moriarty K, Siachos A, Kereiakes D, Traboulssi M, Arif I, Kosinski E, Quadrel M, DeHart D, Miller M, Poock J, Loh I, van Cleeff M, Georgeson S, Suryanarayana P, Cohn J, Schmedtje J, Lamas G, DeSantis J, Stahl L, Prashad R, Schuchard T, Schramm E, Rao V, Deen C, Soufer J, Gurbel P, Vazquez-Tanus J, Srivastava S, Ballantyne C, Lotun K, Younis L, Gupta D, Yeoman G, Zebrack J, Knutson T, Whitaker J, Appel M, Koren M, Muneer B, Fairlamb J, Aviles R, Kozlowski L, Rees A, Stephens M, Mays M, Downey H, Almassi H, Peichert D, Rocco M, French W, Bhatia P, Hoch J, Peart B, Carmichael P, Acheatel R, Vo A, Kirtane A, Bhagwat R, Gilchrist I, Labroo A, Pollock S, Bacon J, Karunaratne H, Moursi M, Doshi A, Sethi P, Treasure C, Marple R, Goodwin T, Zayas-Torres C, Loussararian A, Korn D, Paster R, Albirini A, Moretto T, Guarnieri T, White L, Kramer J, Shortal B, Maynard K, Raikhel M, Rohatgi A, Melucci M, Masri B, Krichmar P, Morris F, Canto J, Wali A, Comerota A, Ellison W, Degregorio M, Chandrika Parameswaran A, Goldscher D, George W, Mulkay A, Maynard R, Ziada K, Strain J, Hermiller J, Ennis B, Desai V, Al-Joundi B, Azocar J, Claudio J, Perez Vargas E, Loy J, Albert M, Chandler G, Maislos F, Graf R, Rama P, Studeny M, Gimple L, Pytlewski G, Simon H, Islam A, Dillon W, Shah S, Geohas C., Lincoff, Am, Nicholls, Sj, Riesmeyer, J, Barter, Pj, Brewer, Hb, Fox, Kaa, Gibson, Cm, Granger, C, Menon, V, Montalescot, G, Rader, D, Tall, Ar, Mcerlean, E, Wolski, K, Ruotolo, G, Vangerow, B, Weerakkody, G, Goodman, Sg, Conde, D, Mcguire, Dk, Nicolau, Jc, Leiva-Pons, Jl, Pesant, Y, Li, W, Kandath, D, Kouz, S, Tahirkheli, N, Mason, D, Nissen, Se, Del Valle, M, Finnell, Jb, Standley, J, Poi, K, Croaning, J, Tong, Yc, Guerra, Jl, Guasparini, G, Hubert, C, Ardissino, D, Betteridge, J, Borghi, C, Bruckert, E, Chiang, Ce, Cinteza, M, Dalby, Aj, Erlinge, D, Fernandez-Ortiz, A, Ge, J, Gottlieb, S, Goudev, A, Gratsiansky, N, Huber, K, Ilavská, A, Jeong, Mh, Jukema, Jw, Katus, H, Keltai, M, Krum, H, Nielsen, H, Ogawa, H, Ongen, Z, Parkhomenko, A, Raugaliene, R, Renkin, J, Rynkiewicz, A, Steinhubl, S, White, H, Widimsky, P, Zhu, J, Armstrong, P, Ridker, P, Mahaffey, K, Steg, G, Wittes, J, Bhargava, A, Chenier, M, Coleman, C, Cremer, P, Jellis, C, Lahoud, R, Lappe, J, Min, D, Monteleone, P, Newton, D, Stegman, B, Senn, T, Katzan, I, Sharma, J, Uchino, K, Vora, N, Brown, K, Fabec, D, Piper, P, Preston, S, Colombo, T, Pagel-Langenickel, I, Penev, P, Maixing, A, Crowley, K, Sarkar, S, Torosyan, N, Castano, L, Tran, D, Dena, V, Blain, L, Keenan, G, Slade, K, Quinlan, E, Edwards, R, Ren, H, Glenny, J, Maffei, L, Albisu Di Gennaro, J, Caccavo, A, Prado, A, Colombo, H, Luquez, H, Lobo Marquez, L, Hammett, C, Blombery, P, Colquhoun, D, Amerena, J, Howes, L, Cooke, D, Simpson, R, Horowitz, J, Sullivan, D, Proietto, J, Yeo, W, Hirschl, M, Hanusch, U, Drexel, H, Brodmann, M, Wollaert, B, De Wolf, L, Delforge, M, Vanwelden, J, Peeters, A, Siqueira Bodart, J, Montenegro, R, Franken, M, Eliaschewitz, F, Parvanova, Z, Raev, D, Mincheva, V, Kichukov, K, Stoyanov, M, Apostolova, E, Tzekova, M, Dimov, B, Lazov, P, Devedzhiev, T, Dion, D, Poirier, P, Lavoie, Jp, Lonn, E, Shukla, D, Chehayeb, R, Nault, P, Gaudet, D, Tardif, Jc, Beaudry, Y, Bakbak, A, Wong, B, St-Maurice, F, Labonte, R, Polasek, P, Sweet, M, Bhargava, R, Nawaz, S, Pandey, S, Tishler, S, Peterson, S, O’Keefe, D, Genest, J, Syan, R, Leiter, L, Li, H, Ma, W, Ma, C, Xu, D, Li, X, Hala, T, Machova, V, Smejkalova, O, Vodnansky, P, Reichert, P, Velimsky, T, Matuska, J, Machkova, M, Jerabek, O, Kuchar, J, Rasmussen, T, Lindgren, L, Alexandersen, P, Bang, L, Brønnum-Schou, J, Valter, I, Soots, M, Lanno, R, Rosenthal, S, Cottin, Y, Elbaz, M, Lafitte, S, Silvain, J, Coste, P, Rangé, G, Gosse, P, Morel, O, Berrouschot, J, Bourhaial, H, Toursarkissian, N, Appel, Kf, Rieker, W, Stellbrink, C, Münzel, T, Geisler, T, Kadel, C, Giannitsis, E, Trenk, D, vom Dahl, J, Dorsel, T, Singer, O, Schäufele, T, Natour, M, Ozaki, R, Lau, E, Chan, K, Yeung, V, Yu, C, Lakatos, F, Zólyomi, S, Vangel, S, Merkely, B, Szakal, I, Sipos, A, Laszloczky, A, Kis, E, Szocs, A, Szántai, G, Faludi, P, Kancz, S, Oroszlan, T, Hamoud, S, Francis, A, Chorin, E, Leibowitz, D, Kracoff, O, Weisz, G, Schiff, E, Bitzur, R, Hussein, O, Di Lorenzo, L, Visona, A, Mos, L, De Luca, G, Salvioni, A, Rubba, P, Imberti, D, Bucci, M, Saku, K, Sueyoshi, A, Ohshima, K, Kazatani, Y, Shimizu, M, Fujii, K, Higa, N, Kawamitsu, K, Shimomura, H, Hoshizaki, H, Tashiro, H, Baden, M, Ueda, O, Tanabe, J, Momiyama, Y, Hosokawa, S, Takahashi, N, Kimura, K, Fujinaga, H, Masutani, M, Kuramochi, T, Higashikata, T, Ichikawa, S, Yamagishi, M, Sakota, S, Sakuragi, S, Suzuki, M, Taguchi, S, Nakamura, T, Ozaki, Y, Tsujita, K, Yasuda, S, Ando, K, Fujimoto, K, Tanabe, K, Fukunaga, M, Kavaliauskiene, R, Motiejuniene, L, Slapikas, R, Jarasuniene, D, De los Rios Ibarra, M, Alcocer Gamba, M, Nevarez Ruiz, L, Fajardo-Campos, P, Llamas Esperon, G, Violante Ortiz, R, Stobschinski de Alba, C, Guizar Sanchez, C, Guerra Lopez, A, Montano, E, Miracle, S, Fanghanel, G, Lenderink, T, Troquay, R, Van Leendert, R, van Eck, J, Hamer, B, Ronner, E, Karalis, I, Lok, D, Magro, M, Westendorp, I, Stroes, E, De Melker, E, Verhave, G, Plomp, J, Bronzwaer, P, Wiersma, J, Kooy, A, Herrman, Jp, Imholz, B, de Groot, M, Devlin, G, Elliott, J, Benatar, J, Harding, S, Hart, H, C, Young, Mirek-Bryniarska, E, Gniot, J, Broncel, M, Kozina, M, Kus, W, Sciborski, R, Lesnik, J, Kawka-Urbanek, T, Krzyzanowski, M, Okopien, B, Wierzbicka, K, Dyczek, A, Ochean, V, Copaci, I, Matei, C, Pruna, C, Constantinescu, M, Minescu, B, Stamate, C, Boldueva, S, Markov, V, Alexeeva, N, Chizhov, P, Supryadkina, T, Petrochenkova, N, Zrazhevsky, K, Barbarash, O, Gurevich, V, Hranai, M, Gergel, V, Dzupina, A, Uhliar, R, Vinanska, D, Fazekas, F, Bugan, W, Saaiman, J, Nortje, H, Theron, H, Bernhardi, D, Ramlachan, P, Van-Zyl, L, Basson, M, Venter, T, Kim, D, Han, S, Park, G, Hwang, K, Rhee, M, Cho, B, Jeong, J, Hong, B, Chang, K, Garcia Puig, J, Fuentes Jiménez, F, Nieto Iglesias LJ, Pintó Sala, X, Gamez, Jm, Sánchez Álvarez, J, Hernandez García JM, Olsson, A, Mooe, T, Tengmark, Bo, Lindholm, Cj, Hansen, O, Tyden, P, Moccetti, T, Binder, R, Ueng, K, Lai, W, Shyu, K, Hsieh, I, Sheu, W, Chen, J, Altunkeser, B, Erkan, A, Karpenko, O, Kaydashev, I, Yagensky, A, Kovalenko, V, Brunskill, J, Barr, C, Cecil, J, Cahill, T, A Gorog D, Bakhai, A, Coulson, W, Gorog, D, Loftus, I, Haddad, T, Hotchkiss, D, Isserman, S, Janik, M, Weinstein, D, Wilson, S, Butman, S, Hearne, S, Khan, F, Nadar, V, Zelman, R, R, Benton, E, Flore, Kahn, B, Soni, A, Asbill, B, Singal, D, Dy, J, Foucauld, J, Crenshaw, B, Rogers, W, Aslam, A, Lieber, I, Shah, P, Durr, S, Spencer, R, Mahal, S, Cheng, S, Abadier, R, Gilmore, R, Staniloae, C, Miller, G, Seals, A, Jetty, P, Mathis, C, Henry, S, Murray, A, Felten, W, Navas, J, Gudipati, R, Singh, N, West, S, Sabatino, K, Crater, T, Amin, J, Dosh, K, Earl, J, Z Jafar M, Gelernt, M, Kutner, M, J, Salazar, Krantzler, J, El-Ahdab, F, Lader, E, Zakhary, B, Miller, S, Madder, R, Khan, T, Khan, M, Collis, W, Evans, J, Prodafikas, J, Panchal, V, Cohen, K, Weiss, R, Dietrich, D, Vogel, C, Mascarenhas, V, Seaworth, J, Teklinski, A, Davalos, J, Dehning, M, Herzog, W, Snyder, H, Talano, J, Donahoe, S, Hunter, J, Sandoval, J, Batchelor, W, Brautigam, D, Moriarty, K, Siachos, A, Kereiakes, D, Traboulssi, M, Arif, I, Kosinski, E, Quadrel, M, Dehart, D, Miller, M, Poock, J, Loh, I, van Cleeff, M, Georgeson, S, Suryanarayana, P, Cohn, J, Schmedtje, J, Lamas, G, Desantis, J, Stahl, L, Prashad, R, Schuchard, T, Schramm, E, Rao, V, Deen, C, Soufer, J, Gurbel, P, Vazquez-Tanus, J, Srivastava, S, Ballantyne, C, Lotun, K, Younis, L, Gupta, D, Yeoman, G, Zebrack, J, Knutson, T, Whitaker, J, Appel, M, Koren, M, Muneer, B, Fairlamb, J, Aviles, R, Kozlowski, L, Rees, A, Stephens, M, Mays, M, Downey, H, Almassi, H, Peichert, D, Rocco, M, French, W, Bhatia, P, Hoch, J, Peart, B, Carmichael, P, Acheatel, R, Vo, A, Kirtane, A, Bhagwat, R, Gilchrist, I, Labroo, A, Pollock, S, Bacon, J, Karunaratne, H, Moursi, M, Doshi, A, Sethi, P, Treasure, C, Marple, R, Goodwin, T, Zayas-Torres, C, Loussararian, A, Korn, D, Paster, R, Albirini, A, Moretto, T, Guarnieri, T, White, L, Kramer, J, Shortal, B, Maynard, K, Raikhel, M, Rohatgi, A, Melucci, M, Masri, B, Krichmar, P, Morris, F, Canto, J, Wali, A, Comerota, A, Ellison, W, Degregorio, M, Chandrika Parameswaran, A, Goldscher, D, George, W, Mulkay, A, Maynard, R, Ziada, K, Strain, J, Hermiller, J, Ennis, B, Desai, V, Al-Joundi, B, Azocar, J, Claudio, J, Perez Vargas, E, Loy, J, Albert, M, Chandler, G, Maislos, F, Graf, R, Rama, P, Studeny, M, Gimple, L, Pytlewski, G, Simon, H, Islam, A, Dillon, W, Shah, S, Geohas, C., Lincoff, A. Michael, Nicholls, Stephen J., Riesmeyer, Jeffrey S., Barter, Philip J., Brewer, H. Bryan, Fox, Keith A. A., Gibson, C. Michael, Granger, Christopher, Menon, Venu, Montalescot, Gille, Rader, Daniel, Tall, Alan R., Mcerlean, Ellen, Wolski, Kathy, Ruotolo, Giacomo, Vangerow, Burkhard, Weerakkody, Govinda, Goodman, Shaun G., Conde, Diego, Mcguire, Darren K., Nicolau, Jose C., Leiva-Pons, Jose L., Pesant, Yve, Li, Weimin, Kandath, David, Kouz, Simon, Tahirkheli, Naeem, Mason, Denise, Nissen, Steven E., Del Valle M, Young, C, Nieto Iglesias, Lj, Hernandez García, Jm, A Gorog, D, Benton, R, Flores, E, Z Jafar, M, and Salazar, J
Subjects: Male, 0301 basic medicine, Cardiovascular Outcome, Cholesterol Ester Transfer Protein, Myocardial Ischemia, 030204 cardiovascular system & hematology, Coronary artery disease, cholesteryl ester transfer protein inhibitor, Benzodiazepines, chemistry.chemical_compound, 0302 clinical medicine, Cardiovascular Disease, Anticholesteremic Agent, Intracranial Arteriosclerosi, Treatment Failure, Evacetrapib, Peripheral Vascular Diseases, Benzodiazepine, biology, Medicine (all), Anticholesteremic Agents, Diabetes Mellitu, General Medicine, Middle Aged, Intracranial Arteriosclerosis, High-Risk Vascular Disease, Editorial, Cardiovascular Diseases, Cardiology, Female, lipids (amino acids, peptides, and proteins), Human, Risk, medicine.medical_specialty, Acute coronary syndrome, 03 medical and health sciences, Double-Blind Method, Internal medicine, Diabetes mellitus, Cholesterylester transfer protein, Diabetes Mellitus, Journal Article, medicine, Humans, Aged, Cholesterol, Vascular disease, business.industry, Cholesterol, HDL, Biomarker, Cholesterol, LDL, medicine.disease, Cholesterol Ester Transfer Proteins, Surgery, 030104 developmental biology, Peripheral Vascular Disease, chemistry, biology.protein, business, Biomarkers, Lipoprotein
Abstract: BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .).
Published: 2017

24. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author: Erzurumluoglu, AM, Liu, M, Jackson, VE, Barnes, DR, Datta, G, Melbourne, CA, Young, R, Batini, C, Surendran, P, Jiang, T, Adnan, SD, Afaq, S, Agrawal, A, Altmaier, E, Antoniou, AC, Asselbergs, FW, Baumbach, C, Beirut, L, Bertelsen, S, Boehnke, M, Bots, ML, Brazel, DM, Chambers, JC, Chang-Claude, J, Chen, C, Corley, J, Chou, Y-L, David, SP, de Boer, RA, de Leeuw, CA, Dennis, JG, Dominiczak, AF, Dunning, AM, Easton, DF, Eaton, C, Elliott, P, Evangelou, E, Faul, JD, Foroud, T, Goate, A, Gong, J, Grabe, HJ, Haessler, J, Haiman, C, Hallmans, G, Hammerschlag, AR, Harris, SE, Hattersley, A, Heath, A, Hsu, C, Iacono, WG, Kanoni, S, Kapoor, M, Kaprio, J, Kardia, SL, Karpe, F, Kontto, J, Kooner, JS, Kooperberg, C, Kuulasmaa, K, Laakso, M, Lai, D, Langenberg, C, Le, N, Lettre, G, Loukola, A, Luan, J, Madden, PAF, Mangino, M, Marioni, RE, Marouli, E, Marten, J, Martin, NG, McGue, M, Michailidou, K, Mihailov, E, Moayyeri, A, Moitry, M, Müller-Nurasyid, M, Naheed, A, Nauck, M, Neville, MJ, Nielsen, SF, North, K, Perola, M, Pharoah, PDP, Pistis, G, Polderman, TJ, Posthuma, D, Poulter, N, Qaiser, B, Rasheed, A, Reiner, A, Renström, F, Rice, J, Rohde, R, Rolandsson, O, Samani, NJ, Samuel, M, Schlessinger, D, Scholte, SH, Scott, RA, Sever, P, Shao, Y, Shrine, N, Smith, JA, Starr, JM, Stirrups, K, Stram, D, Stringham, HM, Tachmazidou, I, Tardif, J-C, Thompson, DJ, Tindle, HA, Tragante, V, Trompet, S, Turcot, V, Tyrrell, J, Vaartjes, I, van der Leij, AR, van der Meer, P, Varga, TV, Verweij, N, Völzke, H, Wareham, NJ, Warren, HR, Weir, DR, Weiss, S, Wetherill, L, Yaghootkar, H, Yavas, E, Jiang, Y, Chen, F, Zhan, X, Zhang, W, Zhao, W, Zhou, K, Amouyel, P, Blankenberg, S, Caulfield, MJ, Chowdhury, R, Cucca, F, Deary, IJ, Deloukas, P, Di Angelantonio, E, Ferrario, M, Ferrières, J, Franks, PW, Frayling, TM, Frossard, P, Hall, IP, Hayward, C, Jansson, J-H, Jukema, JW, Kee, F, Männistö, S, Metspalu, A, Munroe, PB, Nordestgaard, BG, Palmer, CNA, Salomaa, V, Sattar, N, Spector, T, Strachan, DP, Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ Consortium, van der Harst, P, Zeggini, E, Saleheen, D, Butterworth, AS, Wain, LV, Abecasis, GR, Danesh, J, Tobin, MD, Vrieze, S, Liu, DJ, and Howson, JMM
Abstract: Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P
Published: 2020

25. Association Between Blood Pressure Variability and Cerebral Small-Vessel Disease: A Systematic Review and Meta-Analysis

Author: Tully, PJ, Yano, Y, Launer, LJ, Kario, K, Nagai, M, Mooijaart, SP, Claassen, JAHR, Lattanzi, S, Vincent, AD, Tzourio, C, Anstey, KJ, Beckett, N, Beiser, AS, Birns, J, Brickman, AM, Burns, NR, Cengiz, M, Cosh, S, de Heus, RAA, de Leeuw, PW, Dorstyn, D, Elias, MF, Jukema, JW, Kikuya, M, Kroon, AA, Mahajan, R, McGrath, ER, Moll van Charante, EP, Ninomiya, T, Ohara, T, Ohkubo, T, Oishi, E, Peters, R, Richard, E, Satoh, M, Selvayanagam, J, Seshadri, S, Stott, DJ, Trompet, S, van Gool, WA, van Middelaar, T, Turnbull, DA, Tully, PJ, Yano, Y, Launer, LJ, Kario, K, Nagai, M, Mooijaart, SP, Claassen, JAHR, Lattanzi, S, Vincent, AD, Tzourio, C, Anstey, KJ, Beckett, N, Beiser, AS, Birns, J, Brickman, AM, Burns, NR, Cengiz, M, Cosh, S, de Heus, RAA, de Leeuw, PW, Dorstyn, D, Elias, MF, Jukema, JW, Kikuya, M, Kroon, AA, Mahajan, R, McGrath, ER, Moll van Charante, EP, Ninomiya, T, Ohara, T, Ohkubo, T, Oishi, E, Peters, R, Richard, E, Satoh, M, Selvayanagam, J, Seshadri, S, Stott, DJ, Trompet, S, van Gool, WA, van Middelaar, T, and Turnbull, DA
Abstract: Background: Research links blood pressure variability (BPV) with stroke; however, the association with cerebral small-vessel disease (CSVD) remains unclear. As BPV and mean blood pressure are interrelated, it remains uncertain whether BPV adds additional information to understanding cerebrovascular morphological characteristics. Methods and Results: A systematic review was performed from inception until March 3, 2019. Eligibility criteria included population, adults without stroke (<4 weeks); exposure, BPV quantified by any metric over any duration; comparison, (1) low versus high or mean BPV and (2) people with versus without CSVD; and outcomes, (1) CSVD as subcortical infarct, lacunae, white matter hyperintensities, cerebral microbleeds, or enlarged perivascular spaces; and (2) standardized mean difference in BPV. A total of 27 articles were meta-analyzed, comprising 12 309 unique brain scans. A total of 31 odds ratios (ORs) were pooled, indicating that higher systolic BPV was associated with higher odds for CSVD (OR, 1.27; 95% CI, 1.14–1.42; I2=85%) independent of mean systolic pressure. Likewise, higher diastolic BPV was associated with higher odds for CSVD (OR, 1.30; 95% CI, 1.14–1.48; I2=53%) independent of mean diastolic pressure. There was no evidence of a pairwise interaction between systolic/diastolic and BPV/mean ORs (P=0.47), nor a difference between BPV versus mean pressure ORs (P=0.58). Fifty-four standardized mean differences were pooled and provided similar results for pairwise interaction (P=0.38) and difference between standardized mean differences (P=0.70). Conclusions: On the basis of the available studies, BPV was associated with CSVD independent of mean blood pressure. However, more high-quality longitudinal data are required to elucidate whether BPV contributes unique variance to CSVD morphological characteristics.
Published: 2020

26. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author: Surendran, P, Feofanova, E, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, A, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Edwards, DRV, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, de Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, T, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, Y, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, A, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Smith, GD, de Boer, RA, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, M, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, J, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, van der Harst, P, van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, D, Levy, D, Newton-Cheh, C, Munroe, PB, Howson, JMM, Surendran, P, Feofanova, E, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, A, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Edwards, DRV, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, de Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, T, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, Y, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, A, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Smith, GD, de Boer, RA, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, M, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, J, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, van der Harst, P, van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, D, Levy, D, Newton-Cheh, C, Munroe, PB, and Howson, JMM
Abstract: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
Published: 2020

27. Cerebral small vessel disease genomics and its implications across the lifespan

Author: Sargurupremraj, M, Suzuki, H, Jian, X, Sarnowski, C, Evans, TE, Bis, JC, Eiriksdottir, G, Sakaue, S, Terzikhan, N, Habes, M, Zhao, W, Armstrong, NJ, Hofer, E, Yanek, LR, Hagenaars, SP, Kumar, RB, van den Akker, EB, McWhirter, RE, Trompet, S, Mishra, A, Saba, Y, Satizabal, CL, Beaudet, G, Petit, L, Tsuchida, A, Zago, L, Schilling, S, Sigurdsson, S, Gottesman, RF, Lewis, CE, Aggarwal, NT, Lopez, OL, Smith, JA, Hernandez, MCV, van der Grond, J, Wright, MJ, Knol, MJ, Dorr, M, Thomson, RJ, Bordes, C, Le Grand, Q, Duperron, M-G, Smith, A, Knopman, DS, Schreiner, PJ, Evans, DA, Rotter, J, Beiser, AS, Maniega, SM, Beekman, M, Trollor, J, Stott, DJ, Vernooij, MW, Wittfeld, K, Niessen, WJ, Soumare, A, Boerwinkle, E, Sidney, S, Turner, ST, Davies, G, Thalamuthu, A, Volker, U, van Buchem, MA, Bryan, RN, Dupuis, J, Bastin, ME, Ames, D, Teumer, A, Amouyel, P, Kwok, JB, Bulow, R, Deary, IJ, Schofield, PR, Brodaty, H, Jiang, J, Tabara, Y, Setoh, K, Miyamoto, S, Yoshida, K, Nagata, M, Kamatani, Y, Matsuda, F, Psaty, BM, Bennett, DA, De Jager, PL, Mosley, TH, Sachdev, PS, Schmidt, R, Warren, HR, Evangelou, E, Tregouet, D-A, Ikram, MA, Wen, W, DeCarli, C, Srikanth, VK, Jukema, JW, Slagboom, EP, Kardia, SLR, Okada, Y, Mazoyer, B, Wardlaw, JM, Nyquist, PA, Mather, KA, Grabe, HJ, Schmidt, H, Van Duijn, CM, Gudnason, V, Longstreth, WT, Launer, LJ, Lathrop, M, Seshadri, S, Tzourio, C, Adams, HH, Matthews, PM, Fornage, M, Debette, S, Sargurupremraj, M, Suzuki, H, Jian, X, Sarnowski, C, Evans, TE, Bis, JC, Eiriksdottir, G, Sakaue, S, Terzikhan, N, Habes, M, Zhao, W, Armstrong, NJ, Hofer, E, Yanek, LR, Hagenaars, SP, Kumar, RB, van den Akker, EB, McWhirter, RE, Trompet, S, Mishra, A, Saba, Y, Satizabal, CL, Beaudet, G, Petit, L, Tsuchida, A, Zago, L, Schilling, S, Sigurdsson, S, Gottesman, RF, Lewis, CE, Aggarwal, NT, Lopez, OL, Smith, JA, Hernandez, MCV, van der Grond, J, Wright, MJ, Knol, MJ, Dorr, M, Thomson, RJ, Bordes, C, Le Grand, Q, Duperron, M-G, Smith, A, Knopman, DS, Schreiner, PJ, Evans, DA, Rotter, J, Beiser, AS, Maniega, SM, Beekman, M, Trollor, J, Stott, DJ, Vernooij, MW, Wittfeld, K, Niessen, WJ, Soumare, A, Boerwinkle, E, Sidney, S, Turner, ST, Davies, G, Thalamuthu, A, Volker, U, van Buchem, MA, Bryan, RN, Dupuis, J, Bastin, ME, Ames, D, Teumer, A, Amouyel, P, Kwok, JB, Bulow, R, Deary, IJ, Schofield, PR, Brodaty, H, Jiang, J, Tabara, Y, Setoh, K, Miyamoto, S, Yoshida, K, Nagata, M, Kamatani, Y, Matsuda, F, Psaty, BM, Bennett, DA, De Jager, PL, Mosley, TH, Sachdev, PS, Schmidt, R, Warren, HR, Evangelou, E, Tregouet, D-A, Ikram, MA, Wen, W, DeCarli, C, Srikanth, VK, Jukema, JW, Slagboom, EP, Kardia, SLR, Okada, Y, Mazoyer, B, Wardlaw, JM, Nyquist, PA, Mather, KA, Grabe, HJ, Schmidt, H, Van Duijn, CM, Gudnason, V, Longstreth, WT, Launer, LJ, Lathrop, M, Seshadri, S, Tzourio, C, Adams, HH, Matthews, PM, Fornage, M, and Debette, S
Abstract: White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
Published: 2020

28. Association of common genetic variants with brain microbleeds: A genome-wide association study

Author: Knol, Maria, Lu, Difei, Traylor, M, Adams, Hieab, Romero, JR, Smith, AV, Fornage, M, Hofer, E, Liu, Jun, Hostettler, IC, Luciano, M, Trompet, S, Giese, A K, Hilal, S, van den Akker, EB, Vojinovic, Dina, Li, S, Sigurdsson, S, van der Lee, Sven, Jack, CR, Wilson, D, Yilmaz, Pinar, Satizabal, CL, Liewald, DCM, van der Grond, J, Chen, C, Saba, Y, van der Lugt, Aad, Bastin, ME, Windham, BG, Cheng, CY (Ching-Yu), Pirpamer, L, Kantarci, K, Himali, JJ, Yang, Q, Morris, Z, Beiser, AS, Tozer, DJ, Vernooij, Meike, Amin, Najaf, Beekman, M, Koh, JY, Stott, DJM, Houlden, H, Schmidt, R, Gottesman, RF, MacKinnon, AD, DeCarli, C, Gudnason, V, Deary, IJ, Duijn, Cornelia, Slagboom, PE, Wong, TY, Rost, NS, Jukema, JW, Mosley, TH, Jr, Werring, DJ, Schmidt, H, Wardlaw, JM, Ikram, Arfan, Seshadri, S, Launer, LJ, Markus, HS, Knol, Maria, Lu, Difei, Traylor, M, Adams, Hieab, Romero, JR, Smith, AV, Fornage, M, Hofer, E, Liu, Jun, Hostettler, IC, Luciano, M, Trompet, S, Giese, A K, Hilal, S, van den Akker, EB, Vojinovic, Dina, Li, S, Sigurdsson, S, van der Lee, Sven, Jack, CR, Wilson, D, Yilmaz, Pinar, Satizabal, CL, Liewald, DCM, van der Grond, J, Chen, C, Saba, Y, van der Lugt, Aad, Bastin, ME, Windham, BG, Cheng, CY (Ching-Yu), Pirpamer, L, Kantarci, K, Himali, JJ, Yang, Q, Morris, Z, Beiser, AS, Tozer, DJ, Vernooij, Meike, Amin, Najaf, Beekman, M, Koh, JY, Stott, DJM, Houlden, H, Schmidt, R, Gottesman, RF, MacKinnon, AD, DeCarli, C, Gudnason, V, Deary, IJ, Duijn, Cornelia, Slagboom, PE, Wong, TY, Rost, NS, Jukema, JW, Mosley, TH, Jr, Werring, DJ, Schmidt, H, Wardlaw, JM, Ikram, Arfan, Seshadri, S, Launer, LJ, and Markus, HS
Published: 2020

29. The dual PPARα/γ agonist tesaglitazar blocks progression of pre-existing atherosclerosis in APOE*3Leiden.CETP transgenic mice

Author: Van Der Hoorn, JWA, Jukema, JW, Havekes, LM, Lundholm, E, Camejo, G, Rensen, PCN, and Princen, HMG
Published: 2009
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30. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (vol 50, pg 524, 2018)

Author: Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, A-K, Van der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, TM, Benavente, OR, Bevan, S, Boncoraglio, GB, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, W-M, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, DeStefano, AL, Den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, F-C, Hyacinth, IH, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jimenez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, J-M, Lemmens, R, Leys, D, Lewis, CM, Lin, W-Y, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmae, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Rotter, JI, Rundek, T, Sacco, RL, Sakaue, S, Sale, MM, Salomaa, V, Sapkota, BR, Schmidt, R, Schmidt, CO, Schminke, U, Sharma, P, Slowik, A, Sudlow, CLM, Tanislav, C, Tatlisumak, T, Taylor, KD, Thijs, VNS, Thorleifsson, G, Thorsteinsdottir, U, Tiedt, S, Trompet, S, Tzourio, C, Van Duijn, CM, Walters, M, Wareham, NJ, Wassertheil-Smoller, S, Wilson, JG, Wiggins, KL, Yang, Q, Yusuf, S, Bis, JC, Pastinen, T, Ruusalepp, A, Schadt, EE, Koplev, S, Bjorkegren, JLM, Codoni, V, Civelek, M, Smith, NL, Tregouet, DA, Christophersen, IE, Roselli, C, Lubitz, SA, Ellinor, PT, Tai, ES, Kooner, JS, Kato, N, He, J, Van der Harst, P, Elliott, P, Chambers, JC, Takeuchi, F, Johnson, AD, Sanghera, DK, Melander, O, Jern, C, Strbian, D, Fernandez-Cadenas, I, Longstreth, WT, Rolfs, A, Hata, J, Woo, D, Rosand, J, Pare, G, Hopewell, JC, Saleheen, D, Stefansson, K, Worrall, BB, Kittner, SJ, Seshadri, S, Fornage, M, Markus, HS, Howson, JMM, Kamatani, Y, Debette, S, and Dichgans, M
Subjects: Genetics & Heredity, International Genomics of Blood Pressure (iGEN-BP) Consortium, COMPASS Consortium, MEGASTROKE Consortium, Science & Technology, UK Young Lacunar DNA Study, AFGen Consortium, INVENT Consortium, STARNET, 06 Biological Sciences, METASTROKE Consortium, EPIC-CVD Consortium, BioBank Japan Cooperative Hospital Group, International Stroke Genetics Consortium (ISGC), NINDS Stroke Genetics Network (SiGN), Neurology Working Group of the CHARGE Consortium, EPIC-InterAct Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Developmental Biology
Published: 2019

31. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Author: Fulcher, J, Mihaylova, B, O'Connell, R, Emberson, J, Blackwell, L, Reith, C, Koren, M, Tonkin, A, Ridker, P, Barnes, E, Ford, I, Kean, S, Trompet, S, Macfarlane, P, Cannon, C, Pedersen, TR, Wilhelmsen, L, LaRosa, J, Packard, C, Robertson, M, Young, R, Tobert, J, Flather, M, Goto, S, Kastelein, J, Newman, C, Shear, C, Varigos, J, White, H, Armitage, J, Davies, K, Halls, H, Harper, C, Herrington, W, Holland, L, Kirby, A, Oconnell, R, Preiss, D, Spata, E, Wilson, K, Lonn, E, Wanner, C, Koenig, W, Gotto, A, Kjekshus, J, Yusuf, S, Collins, R, Simes, J, Baigent, C, Keech, A, De Lemos, J, Braunwald, E, Blazing, M, Murphy, S, Downs, JR, Clearfield, M, Holdaas, H, Gordon, D, Davis, B, Dahlof, B, Poulter, N, Sever, P, Knopp, RH, Fellstrom, B, Jardine, A, Schmieder, R, Zannad, F, Colhoun, HM, Betteridge, DJ, Durrington, PN, Hitman, GA, Fuller, J, Neil, A, Sacks, F, Moye, L, Pfeffer, M, Hawkins, CM, Wedel, H, Wikstrand, J, Krane, V, Tavazzi, L, Maggioni, A, Marchioli, R, Tognoni, G, Franzosi, MG, Bowman, L, Landray, MJ, Parish, S, Peto, R, Sleight, P, Ridker, PM, Macmahon, S, Marschner, I, Shaw, J, Serruys, PW, Nakamura, H, Knatterud, G, Furberg, C, Byington, R, Sattar, N, and Jukema, JW
Subjects: medicine.medical_specialty, Statin, medicine.drug_class, Atorvastatin, 030204 cardiovascular system & hematology, ATORVASTATIN, PURLs®, Rate ratio, Article, 03 medical and health sciences, 0302 clinical medicine, Medicine, General & Internal, Risk Factors, Internal medicine, General & Internal Medicine, medicine, Humans, Rosuvastatin, CORONARY-HEART-DISEASE, 030212 general & internal medicine, Myocardial infarction, ROSUVASTATIN, Stroke, ELDERLY-PATIENTS, Aged, Randomized Controlled Trials as Topic, Aged, 80 and over, RISK, Science & Technology, Cholesterol Treatment Trialists' Collaboration, Vascular disease, business.industry, CHOLESTEROL, Age Factors, General Medicine, 11 Medical And Health Sciences, medicine.disease, R1, 3. Good health, LOWERING THERAPY, Regimen, MYOCARDIAL-INFARCTION, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, PRIMARY PREVENTION, Life Sciences & Biomedicine, medicine.drug
Abstract: Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages.Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence.Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials.Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation.
Published: 2019

32. Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome ODYSSEY OUTCOMES Trial

Author: Jukema, JW, Szarek, M, Zijlstra, LE (Laurien), de Silva, HA, Bhatt, DL, Bittner, VA, Simoons, Maarten, Sijbrands, E.J.G., Picault, P, Zobouyan, I, Cardiology, and Internal Medicine
Published: 2019

33. Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery

Author: Szarek, M, Bhatt, DL, Bittner, VA, Diaz, R, Edelberg, JM, Hanotin, C, Harrington, RA, Jukema, JW, Letierce, A, Moryusef, A, Pordy, R, Lopez, GAR, Roe, MT, White, HD, Zeiher, AM, Steg, PG, Schwartz, GG, Aylward, PE, Drexel, H, Sinnaeve, P, Dilic, M, Goodman, SG, Prieto, JC, Yong, H, Lopez-Jaramillo, P, Pecin, I, Reiner, Z, Ostadal, P, Poulsen, SH, Viigimaa, M, Nieminen, MS, Danchin, N, Chumburidze, V, Tse, HF, Xavier, D, Zahger, D, Valgimigli, M, Kimura, T, Kim, HS, Kim, SH, Erglis, A, Laucevicius, A, Kedev, S, Yusoff, K, Alings, M, Halvorsen, S, Flores, RMC, Sy, RG, Budaj, A, Morais, J, Dorobantu, M, Karpov, Y, Ristic, AD, Chua, T, Murin, J, Fras, Z, Tunon, J, de Silva, HA, Muller, C, Ray, KK, Vogel, R, Chaitman, B, Kelsey, SF, Olsson, AG, Rouleau, JL, Simoons, ML, Alexander, K, Meloni, C, Rosenson, R, Sijbrands, EJG, Alexander, JH, Armaganijan, L, Bagai, A, Bahit, MC, Brennan, JM, Clifton, S, DeVore, AD, Deloatch, S, Dickey, S, Dombrowski, K, Ducrocq, G, Eapen, Z, Endsley, P, Eppinger, A, Hess, CN, Hlatky, MA, Jordan, JD, Knowles, JW, Kolls, BJ, Kong, DF, Leonardi, S, Lillis, L, Maron, DJ, Marcus, J, Mathews, R, Mehta, RH, Mentz, RJ, Moreira, HG, Patel, CB, Pereira, SB, Perkins, L, Povsic, TJ, Puymirat, E, Jones, WS, Shah, BR, Sherwood, MW, Stringfellow, K, Sujjavanich, D, Toma, M, Trotter, C, van Diepen, SFP, Wilson, MD, Yan, ATK, Schiavi, LB, Garrido, M, Alvarisqueta, AF, Sassone, SA, Bordonava, AP, De Lima, AEA, Schmidberg, JM, Duronto, EA, Caruso, OC, Novaretto, LP, Hominal, MA, Montana, OR, Caccavo, A, Vilamajo, OAG, Lorenzatti, AJ, Cartasegna, LR, Paterlini, GA, Mackinnon, IJ, Caime, GD, Amuchastegui, M, Codutti, OR, Jure, HO, Bono, JOE, Hrabar, AD, Vallejos, JA, Rodolfo, AAG, Novoa, F, Patocchi, CA, Zaidman, CJ, Giuliano, ME, Dran, RD, Vico, ML, Carnero, GS, Guzman, PN, Allende, JCM, Brasca, DFG, Labarta, MHB, Nani, S, Blumberg, EDS, Colombo, HR, Liberman, A, Luciardi, HL, Waisman, GD, Berli, MA, Duran, ROG, Cestari, HG, Luquez, HA, Giordano, JA, Saavedra, SS, Waites, JH, Collins, N, Soward, A, Hii, CLS, Shaw, J, Arstall, MA, Horowitz, J, Rogers, JF, Colquhoun, D, Flores, REO, Roberts-Thomson, P, Raffel, O, Lehman, SJ, Coverdale, SGM, Garrahy, PJ, Starmer, G, Sader, M, Carroll, PA, Zweiker, R, Hoppe, U, Huber, K, Berger, R, Weidinger, F, Faes, D, Hermans, K, Pirenne, B, Leone, A, Hoffer, E, Vrolix, MCM, De Wolf, L, Wollaert, B, Castadot, M, Dujardin, K, Beauloye, C, Vervoort, G, Striekwold, H, Convens, C, Roosen, J, Barbato, E, Claeys, M, Cools, F, Terzic, I, Barakovic, F, Midzic, Z, Pojskic, B, Fazlibegovic, E, Durak-Nalbantic, A, Vulic, D, Muslibegovic, A, Reis, G, Sousa, L, Nicolau, JC, Giorgeto, FE, Silva, RP, Maia, LN, Rech, R, Rossi, PRF, Cerqueira, MJAG, Duda, N, Kalil, R, Kormann, A, Abrantes, JAM, Pimentel, P, Soggia, AP, de Santos, MON, Neuenschwander, F, Bodanese, LC, Michalaros, YL, Eliaschewitz, FG, Vidotti, MH, Leaes, PE, Botelho, RV, Kaiser, S, Manenti, ERFF, Precoma, DB, Jorge, JCM, Silva, PGMD, Silveira, JA, Saporito, W, Marin, JA, Feitosa, GS, Ritt, LEF, de Souza, JA, Costa, F, Souza, WKSB, Reis, HJL, Lopes, RD, Machado, L, Ayoub, JCA, Todorov, GV, Nikolov, FP, Velcheva, ES, Tzekova, ML, Benov, HO, Petranov, SL, Tumbev, HS, Shehova-Yankova, NS, Markov, DT, Raev, DH, Mollov, MN, Kichukov, KN, Ilieva-Pandeva, KA, Gotcheva, NN, Ivanova, R, Mincheva, VM, Lazov, PV, Dimov, BI, Senaratne, M, Stone, J, Kornder, J, Pearce, S, Dion, D, Savard, D, Pesant, Y, Pandey, A, Robinson, S, Gosselin, G, Vizel, S, Hoag, G, Bourgeois, R, Morisset, A, Sabbah, E, Sussex, B, Kouz, S, MacDonald, P, Diaz, A, Michaud, N, Fell, D, Leung, R, Vuurmans, T, Lai, C, Nigro, F, Davies, R, Nogareda, G, Vijayaraghavan, R, Ducas, J, Lepage, S, Mehta, S, Cha, J, Dupuis, R, Fong, P, Rodes-Cabau, J, Fadlallah, H, Cleveland, D, Huynh, T, Bata, I, Hameed, A, Pincetti, C, Potthoff, S, Acevedo, M, Aguirre, A, Vejar, M, Yanez, M, Araneda, G, Fernandez, M, Perez, L, Varleta, P, Florenzano, F, Huidobro, L, Raffo, CA, Olivares, C, Chen, JY, Dong, YG, Huang, WJ, Wang, JZ, Huang, SA, Yao, ZH, Cui, L, Lin, WH, Sun, YM, Wang, JF, Li, JP, Zhang, XL, Zhu, H, Chen, DD, Huang, L, Dong, SH, Su, GH, Xu, B, Su, X, Cheng, XS, Lin, JX, Zong, WX, Li, HM, Feng, Y, Xu, DL, Yang, XC, Ke, YN, Lin, XF, Zhang, Z, Zheng, ZQ, Luo, ZR, Chen, YD, Ding, CH, Zheng, Y, Li, XD, Peng, DQ, Li, Y, Wei, M, Liu, SW, Yu, YH, Qu, BM, Jiang, WH, Zhou, YJ, Zhao, XS, Yuan, ZY, Guo, Y, Xu, XP, Shi, XB, Ge, JB, Fu, GS, Bai, F, Fang, WY, Shou, XL, Yang, XJ, Wang, JA, Jaramillo, N, Vallejo, GS, Botia, DCL, Lopez, RB, De Salazar, DIM, Bonfanti, AJC, Higuera, JD, Silva, SIB, Lozada, HJG, Arroyo, JAC, Mendoza, JLA, Ruiz, RLF, Fernandez, AM, Jatin, FGM, Herazo, AS, Parada, JC, Triana, MAU, Spinar, J, Horak, D, Stasek, J, Alan, D, Machova, V, Linhart, A, Novotny, V, Kaucak, V, Rokyta, R, Naplava, R, Coufal, Z, Adamkova, V, Podpera, I, Zizka, J, Motovska, Z, Marusincova, I, Svab, P, Heinc, P, Kuchar, J, Povolny, P, Raungaard, B, Clemmensen, P, Bang, LE, May, O, Bottcher, M, Hove, JD, Frost, L, Gislason, G, Larsen, J, Johansen, PB, Hald, F, Jeppesen, J, Nielsen, T, Kristensen, KS, Walichiewicz, PM, Lomholdt, JD, Klausen, IC, Nielsen, PK, Davidsen, F, Videbaek, L, Soots, M, Vahula, V, Hedman, A, Soopold, U, Martsin, K, Taskinen, MR, Porthan, K, Airaksinen, JK, Juonala, M, Kiviniemi, T, Vikman, S, Posio, P, Taurio, J, Huikuri, H, Kaikkonen, K, Coste, P, Ferrari, E, Morel, O, Montalescot, G, Barone-Rochette, G, Mansourati, J, Cottin, Y, Leclercq, F, Belhassane, A, Delarche, N, Boccara, F, Paganelli, F, Clerc, J, Schiele, F, Aboyans, V, Probst, V, Berland, J, Lefevre, T, Khintibidze, I, Shaburishvili, T, Pagava, Z, Ghlonti, R, Lominadze, Z, Khabeishvili, G, Hemetsberger, R, Rauch-Krohnert, U, Stratmann, M, Appel, KF, Schmidt, E, Omran, H, Stellbrink, C, Dorsel, T, Lianopoulos, E, Marx, R, Zirlik, A, Schellenberg, D, Heitzer, T, Laufs, U, Marx, N, Gielen, S, Winkelmann, B, Behrens, S, Sydow, K, Simonis, G, Muenzel, T, Werner, N, Leggewie, S, Bocker, D, Braun-Dullaeus, R, Toursarkissian, N, Jeserich, M, Weissbrodt, M, Schaeufele, T, Weil, J, Voller, H, Waltenberger, J, Natour, M, Steiner, S, Heidenreich, L, Gremmler, U, Killat, H, Patsilinakos, S, Kartalis, A, Manolis, A, Sionis, D, Liberopoulos, E, Skoumas, I, Athyros, V, Parthenakis, PIF, Hahalis, PIG, Lekakis, J, Xatzitolios, A, Ovando, SRF, Valdovinos, PCM, Benecke, JLA, De Leon, ERR, Yan, BPY, Siu, DCW, Turi, T, Merkely, B, Kiss, RG, Ungi, I, Lupkovics, G, Nagy, L, Katona, A, Edes, I, Muller, G, Horvath, I, Kapin, T, Falukozy, J, Kumbla, M, Sandhu, M, Annam, S, Proddutur, NR, Premchand, RK, Mahajan, A, Abhyanakar, AD, Kerkar, P, Govinda, RA, Oomman, A, Sinha, D, Patil, SN, Kahali, D, Sawhney, J, Joshi, AB, Chaudhary, S, Harkut, P, Guha, S, Porwal, S, Jujjuru, S, Pothineni, RB, Monteiro, MR, Khan, A, Iyengar, SS, Grewal, JS, Chopda, M, Fulwani, MC, Patange, A, Chopra, VK, Goyal, NK, Shinde, R, Manakshe, GV, Patki, N, Sethi, S, Munusamy, V, Karna, S, Adhyapak, S, Pandurangi, U, Mathur, R, Kalashetti, S, Bhagwat, A, Raghuraman, B, Yerra, SK, Bhansali, P, Borse, R, Das, S, Abdullakutty, J, Saathe, S, Palimkar, P, Atar, S, Shechter, M, Mosseri, M, Arbel, Y, Lotan, C, Rosenschein, U, Katz, A, Henkin, Y, Francis, A, Klutstein, M, Nikolsky, E, Turgeman, Y, Halabi, M, Kornowski, R, Jonas, M, Amir, O, Rozenman, Y, Fuchs, S, Hussein, O, Gavish, D, Vered, Z, Caraco, Y, Elias, M, Tov, N, Piovaccari, G, De Pellegrin, A, Guardigli, G, Licciardello, G, Auguadro, C, Cuccia, C, Salvioni, A, Musumeci, G, Calabro, P, Novo, S, Faggiano, P, De Cesare, NB, Berti, S, Cavallini, C, Puccioni, E, Galvani, M, Tespili, M, Piatti, P, Palvarini, M, De Luca, G, Violini, R, De Leo, A, Filardi, PP, Ferratini, M, Dai, K, Kamiya, H, Ando, K, Takeda, Y, Morino, Y, Hata, Y, Kimura, K, Kishi, K, Michishita, I, Uehara, H, Higashikata, T, Hirayama, A, Hirooka, K, Sakagami, S, Taguchi, S, Koike, A, Fujinaga, H, Koba, S, Kozuma, K, Kawasaki, T, Ono, Y, Shimizu, M, Katsuda, Y, Wada, A, Shinke, T, Ako, J, Fujii, K, Takahashi, T, Sakamoto, T, Furukawa, Y, Sugino, H, Mano, T, Utsu, N, Ito, K, Haraguchi, T, Ueda, Y, Nishibe, A, Fujimoto, K, Yoon, JH, Park, HS, Chae, IH, Kim, MH, Jeong, MH, Rha, S, Kim, C, Hong, T, Busmane, A, Pontaga, N, Strelnieks, A, Mintale, I, Sime, I, Petrulioniene, Z, Kavaliauskiene, R, Jurgaitiene, R, Sakalyte, G, Slapikas, R, Norkiene, S, Misonis, N, Kibarskis, A, Kubilius, R, Bojovski, S, Lozance, N, Kjovkaroski, A, Doncovska, S, Ong, TK, Kasim, S, Maskon, O, Kandasamy, B, Liew, HB, Mohamed, WMIW, Castillo, AG, Calvillo, JC, Campos, PF, Fragoso, JCN, Llamas, EAB, Gamba, MAA, Madrigal, JC, Salas, LGG, Rosas, EL, Diaz, BG, Vazquez, ES, Ackar, AN, Esperon, GAL, Sanchez, CRM, De Leon, MG, Otero, RS, Salmon, GF, Rios, JAP, Ruiz, JAG, Breedveld, RW, Hoogslag, PAM, Suryapranata, H, Oomen, A, Wiersma, JJ, Van Der Wal, RMA, Van Huysduynen-Monraats, PSH, Karalis, I, Verdel, GJE, Brueren, BRG, Troquay, RPT, Viergever, EP, Al-Windy, NYY, Bartels, GL, Cornel, JH, Hermans, WRM, Herrman, JPR, Bos, RJ, Groutars, RGEJ, Van Der Zwaan, CC, Kaplan, R, Ronner, E, Groenemeijer, BE, Bronzwaer, PNA, Liem, AAH, Rensing, BJWM, Bokern, MJJA, Nijmeijer, R, Hersbach, FMRJ, Willems, FF, Gosselink, ATM, Elliott, J, Wilkins, G, Fisher, R, Scott, D, Hart, H, Stewart, R, Harding, S, Ternouth, I, Fisher, N, Aitken, D, Anscombe, R, Tomala, T, Nygard, O, Sparby, JA, Andersen, K, Gullestad, L, Jortveit, J, Munk, PS, Hurtig, U, Ticona, JRC, Velasquez, JRD, Miguel, SAN, Perez, ESS, Chambilla, JMC, Ayala, CAC, Leon, RPC, Gonzales, RJV, Zuniga, JDH, Cosavalente, LAC, Mannucci, JEB, Navarro, NCL, Concha, YMR, Chavez, VER, Hernandez, HAA, Nunez, CAZ, Ferrolino, A, Sy, RAG, Tirador, L, Matiga, G, Coching, RM, Bernan, A, Rogelio, G, Morales, DD, Tan, E, Wlodarczak, A, Jaworska, K, Skonieczny, G, Pawlowicz, L, Wojewoda, P, Busz-Papiez, B, Bednarski, J, Goch, A, Staneta, P, Dulak, E, Saminski, K, Krasowski, W, Sudnik, W, Zurakowski, A, Skorski, M, Lysek, R, Miklaszewicz, B, Kubica, J, Lipko, JA, Kostarska-Srokosz, E, Piepiorka, M, Drzewiecka, A, Sciborski, R, Stasiewski, A, Blicharski, T, Bystryk, L, Szpajer, M, Korol, M, Czerski, T, Mirek-Bryniarska, E, Gniot, J, Lubinski, A, Gorny, J, Franek, E, Monteiro, P, Bastos, JM, Pereira, HH, Martins, D, Seixo, F, Mendonca, C, Botelho, A, Minescu, B, Istratoaie, O, Tesloianu, DN, Cristian, G, Podoleanu, CGC, Constantinescu, MCA, Bengus, CM, Militaru, C, Rosu, D, Parepa, IR, Matei, AV, Alexandru, TM, Shvarts, Y, Orlikova, O, Kobalava, Z, Barbarash, OL, Markov, V, Lyamina, N, Gordienko, A, Zrazhevsky, K, Vishnevsky, AY, Gurevich, V, Stryuk, R, Lomakin, NV, Bokarev, I, Shalaev, S, Khaisheva, L, Chizhov, P, Viktorova, I, Osokina, N, Akatova, E, Chumakova, G, Libov, I, Voevoda, MI, Tretyakova, TV, Baranov, E, Shustov, S, Yakushin, S, Gordeev, I, Khasanov, N, Reshetko, O, Sotnikova, T, Molchanova, O, Nikolaev, K, Gapon, L, Baranova, E, Shogenov, Z, Kosmachova, E, Povzun, A, Egorova, L, Tyrenko, VV, Ivanov, IG, Simic, D, Ivanovic, N, Davidovic, G, Tasic, N, Asanin, MR, Stojic, S, Apostolovic, SR, Ilic, S, Putnikovic, B, Stankovic, A, Arandjelovic, A, Radovanovic, S, Balinovac, J, Dincic, DV, Seferovic, P, Dodic, S, Dimkovic, S, Poh, KK, Ong, HY, Micko, K, Nociar, J, Pella, D, Fulop, P, Hranai, M, Palka, J, Mazur, J, Majercak, I, Dzupina, A, Fazekas, F, Gonsorcik, J, Bugan, V, Selecky, J, Kamensky, G, Strbova, J, Smik, R, Dukat, A, Zuran, I, Oklukar, J, Suligoj, NC, Cevc, M, Lipar, L, Cyster, HP, Ranjith, N, Corbett, C, Bayat, J, Makotoko, EM, Kapp, IE, Basson, MMD, Lottering, H, Van Zyl, LJ, Sebastian, PJ, Pillay, T, Saaiman, JA, Commerford, PJ, Cassimjee, S, Ebrahim, IO, Sarvan, M, Mynhardt, JH, Dalby, AJ, Reuter, H, Moodley, R, Vida, M, Fillat, ARC, Peris, VB, Jimenez, FF, Marin, F, Fernandez, JMC, Gil-Extremera, B, Diz, FW, Garcia-Dorado, D, Iniguez, A, Fernandez, JT, Gonzalez-Juanatey, JR, Portales, JF, Murillo, FC, Pericas, LM, Zamorano, JL, Martin, MD, Cortada, JB, Martin, JJA, Fernandez, JRD, Fernandez, JFD, Lledo, JAG, Sales, JC, Rodriguez, JB, Tragant, GG, Benedicto, A, Gonzalez-Juanatey, C, Potau, MC, Perez, IP, De La Tassa, CM, Rincon, PLO, Recena, JB, Escudier, JM, Constantine, G, Haniffa, R, Tissera, N, Amarasekera, S, Fernando, N, Jayawardena, J, Santharaj, W, Ekanayaka, R, Mendis, S, Senaratne, V, Mayurathan, G, Sirisena, T, Rajapaksha, A, Herath, JI, Amarasena, N, Berglund, S, Rasmanis, G, Hagstrom, E, Witt, N, Mourtzinis, G, Nicol, P, Hansen, O, Romeo, S, Torstensson, I, Jensen, SA, Ahremark, U, Sundelin, T, Moccetti, T, Mach, F, Binder, R, Chiang, CE, Tsai, WC, Ueng, KC, Lai, WT, Liu, ME, Hwang, JJ, Yin, WH, Hsieh, IC, Kuo, JY, Huang, TY, Fang, CY, Kaewsuwanna, P, Soonfuang, W, Jintapakorn, W, Sukonthasarn, A, Sritara, P, Wongpraparut, N, Sastravaha, K, Sansanayudh, N, Kehasukcharoen, W, Piyayotai, D, Camsari, A, Kultursay, H, Guneri, S, Mutlu, B, Ersanli, M, Demirtas, M, Kirma, C, Ural, E, Koldas, L, Karpenko, O, Prokhorov, A, Vakaluyk, I, Myshanych, H, Reshotko, D, Batushkin, V, Rudenko, L, Kovalskyi, I, Kushnir, M, Tseluyko, V, Mostovoy, Y, Stanislavchuk, M, Kyiak, Y, Karpenko, Y, Malynovsky, Y, Klantsa, A, Kutniy, O, Amosova, E, Tashchuk, V, Leshchuk, O, Parkhomenko, A, Rishko, M, Kopytsya, M, Yagensky, A, Vatutin, M, Bagriy, A, Barna, OM, Ushakov, O, Dzyak, G, Goloborodko, B, Rudenko, A, Trevelyan, J, Zaman, A, Lee, K, Moriarty, A, Aggarwal, RK, Clifford, P, Wong, YK, Iqbal, SMR, Subkovas, E, Braganza, D, Sarkar, D, Storey, R, Griffiths, H, Mcclure, S, Muthusamy, R, Kurian, J, Levy, T, Barr, C, Kadr, H, Gerber, R, Simaitis, A, Soran, H, Mathur, A, Brodison, A, Oliver, R, Mudawi, T, Reynolds, T, Sharman, D, Butler, R, Wilkinson, P, Lip, GYH, Halcox, J, Vardi, G, Baldari, D, Brabham, D, Treasure, C, Dahl, C, Palmer, B, Wiseman, A, Puri, S, Mohart, AE, Ince, C, Flores, E, Wright, S, Cheng, SC, Rosenberg, M, Rogers, W, Kosinski, E, Forgosh, L, Waltman, J, Khan, M, Shoukfeh, M, Dagher, G, Lieber, I, Kumar, P, East, C, Krichmar, P, White, L, Knickelbine, T, Haldis, T, Gillespie, E, Suh, D, Arif, I, Akhter, F, Carlson, E, D'Urso, M, El-Ahdab, F, Nelson, W, Harris, B, Cohen, S, Carter, L, Sabatino, K, Haddad, T, Malik, A, Rao, S, Mulkay, A, Jovin, I, Klancke, K, Malhotra, V, Devarapalli, SK, Koren, M, Chandna, H, Dodds, G, Janik, M, Moran, J, Sumner, A, Kobayashi, J, Davis, W, Yazdani, S, Pasquini, J, Thakkar, M, Vedere, A, Leimbach, W, Rider, J, Singh, N, Shah, AV, Moriarty, PM, Janosik, D, Pepine, C, Berman, B, Gelormini, J, Daniels, C, Keating, F, Kondo, NI, Shetty, S, Waider, W, Takata, T, Abu-Fadel, M, Shah, V, Aggarwal, R, Izzo, M, Kumar, A, Hattler, B, Link, C, Bortnick, A, Kinzfogl, G, Ghitis, A, Larry, J, Teufel, E, Kuhlman, P, Mclaurin, B, Zhang, WW, Thew, S, Abbas, J, White, M, Ranadive, N, Gring, C, Henderson, D, Schuchard, T, Farhat, N, Kline, G, Mahal, S, Whitaker, J, Speirs, S, Andersen, R, Daboul, N, Horwitz, P, Jafar, Z, Mcgarvey, J, Panchal, V, Voyce, S, Blok, T, Sheldon, W, Azizad, MM, Schmalfuss, C, Picone, M, Herzog, W, Lindsey, J, Nowins, R, Lepor, N, El Shahawy, M, Weintraub, H, Irimpen, A, May, W, Galski, T, Chu, A, Mody, F, Hodes, Z, Fairlamb, J, Lambert, C, Raisinghani, A, Abbate, A, King, M, Carey, C, Gerber, J, Younis, L, Park, H, Vidovich, M, Knutson, T, Friedman, D, Chaleff, F, Loussararian, A, Kimmelstiel, C, Silver, K, Foster, M, Tonnessen, G, Amlani, M, Wali, A, Malozzi, C, Wattanakit, K, O'Donnell, PJ, Singal, D, Jaffrani, N, Banuru, S, Fisher, D, Xenakis, M, Perlmutter, N, Bhagwat, R, Strader, J, Akyea-Djamson, A, Labroo, A, Marais, HJ, Claxton, E, Berk, M, Rossi, P, Joshi, P, Khaira, AS, Kumkumian, G, Lupovitch, S, Purow, J, Welka, S, Hoffman, D, Fischer, S, Soroka, E, Eagerton, D, Pancholy, S, Ray, M, Farrar, M, Pollock, S, French, WJ, Diamantis, S, Gimple, L, Schwartz, S, Pereira, E, Spriggs, D, Strain, J, Vo, A, Chane, M, Hall, J, Vijay, N, Lotun, K, Lester, FM, Nahhas, A, Pope, T, Nager, P, Vohra, R, Bashir, R, Ahmed, H, Berlowitz, M, Fishberg, R, Barrucco, R, Yang, E, Radin, M, Sporn, D, Eisenberg, S, Landzberg, J, Mcgough, M, Turk, S, Schwartz, M, Sundram, PS, Jain, D, Zainea, M, Bayron, C, Karlsberg, R, Lui, H, Keen, W, Westerhausen, D, Khurana, S, Agarwal, H, Birchem, J, Penny, W, Chang, M, Gilbert, JM, Chalavarya, G, Eaton, C, Schmedtje, JF, Christenson, S, Denham, D, Macdonell, A, Gibson, P, Rahman, A, Al Joundi, T, Conrad, G, Kotha, P, Love, M, Giesler, G, Rubenstein, H, Akright, L, Schifferdecker, B, Krawczyk, J, Wells, T, Welker, J, Foster, R, Gilmore, R, Anderson, J, Jacoby, D, Gardner, G, Dandillaya, R, Vora, K, Kostis, J, Hunter, J, Laxson, D, Ball, E, İÜC, and Ege Üniversitesi
Subjects: Male, medicine.medical_specialty, Acute coronary syndrome, alirocumab, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, lipids, PCSK9, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, Double-Blind Method, coronary artery bypass graft, Internal medicine, medicine, Humans, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, Myocardial infarction, cardiovascular diseases, Acute Coronary Syndrome, Coronary Artery Bypass, Alirocumab, Aged, Kardiologi, business.industry, Unstable angina, Hazard ratio, cholesterol, Middle Aged, medicine.disease, surgical procedures, operative, Bypass surgery, Cardiovascular Diseases, Cardiology, Drug Therapy, Combination, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business, Mace
Abstract: Sherwood, Matthew/0000-0002-4305-5883; Taskinen, Marja-Riitta/0000-0002-6229-3588; Leonardi, Sergio/0000-0002-4800-6132; Raffel, Owen C/0000-0001-5470-7050; Muenzel, Thomas/0000-0001-5503-4150; Ersanli, Murat/0000-0003-1847-3087; Gislason, Gunnar H/0000-0002-0548-402X; bastos, jose/0000-0002-9526-3123; Abbate, Antonio/0000-0002-1930-785X; Chumakova, Galina A/0000-0002-2810-6531; Nikolaev, Konstantin/0000-0003-4601-6203; Tse, Hung Fat/0000-0002-9578-7808; Keskin, Kudret/0000-0002-9049-1530; Reshetko, Olga/0000-0003-3107-7636; Podoleanu, Cristian/0000-0001-9987-2519; Aylward, Philip/0000-0002-5358-8552; LETIERCE, Alexia/0000-0001-6679-5772, WOS: 000483334800002, PubMed: 31466614, BACKGROUND Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death. OBJECTIVES This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). METHODS Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. the primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003). RESULTS in each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [ 0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [ 0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]). CONCLUSIONS Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402) (C) 2019 by the American College of Cardiology Foundation., Fondation Assistance Publique-Hopitaux de Paris, Paris, France, The authors thank the patients, study coordinators, and investigators who participated in this trial. Sophie Rushton-Smith, PhD (MedLink Healthcare Communications, London) provided editorial assistance in the preparation of the manuscript (limited to editing for style, referencing, and figure and table editing) and was funded by Fondation Assistance Publique-Hopitaux de Paris, Paris, France.
Published: 2019

34. Effect of Alirocumab on Mortality After Acute Coronary Syndromes An Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial

Author: Steg, PG, Szarek, M, Bhatt, DL, Bittner, VA, Bregeault, M-F, Dalby, AJ, Diaz, R, Edelberg, JM, Goodman, SG, Hanotin, C, Harrington, RA, Jukema, JW, Lecorps, G, Mahaffey, KW, Moryusef, A, Ostadal, P, Parkhomenko, A, Pordy, R, Roe, MT, Tricoci, P, Vogel, R, White, HD, Zeiher, AM, Schwartz, GG, Sasiela, WJ, Tamby, J-F, Aylward, PE, Drexel, H, Sinnaeve, P, Dilic, M, Gotcheva, NN, Prieto, J-C, Yong, H, Lopez-Jaramillo, P, Pecin, I, Reiner, Z, Poulsen, SH, Viigimaa, M, Nieminen, MS, Danchin, N, Chumburidze, V, Marx, N, Liberopoulos, E, Valdovinos, PCM, Tse, H-F, Kiss, RG, Xavier, D, Zahger, D, Valgimigli, M, Kimura, T, Kim, HS, Kim, S-H, Kedev, S, Erglis, A, Laucevicius, A, Yusoff, K, Lopez, R, Ramos Lopez, GA, Alings, M, Halvorsen, S, Correa Flores, RM, Sy, RG, Budaj, A, Morais, J, Dorobantu, M, Karpov, Y, Ristic, AD, Chua, T, Murin, J, Fras, Z, Tunon, J, De Silva, HA, Hagstrom, E, Muller, C, Chiang, C-E, Sritara, P, Guneri, S, Ray, KK, Moriarty, PM, Chaitman, B, Kelsey, SF, Olsson, AG, Rouleau, J-L, Simoons, ML, Alexander, K, Meloni, C, Rosenson, R, Sijbrands, EJG, Alexander, JH, Armaganijan, L, Bagai, A, Bahit, MC, Brennan, JM, Clifton, S, DeVore, AD, Deloatch, S, Dickey, S, Dombrowski, K, Ducrocq, G, Eapen, Z, Endsley, P, Eppinger, A, Harrison, RW, Hess, CN, Hlatky, MA, Jordan, JD, Knowles, JW, Kolls, BJ, Kong, DF, Leonardi, S, Lillis, L, Maron, DJ, Marcus, J, Mathews, R, Mehta, RH, Mentz, RJ, Moreira, HG, Patel, CB, Pereira, SB, Perkins, L, Povsic, TJ, Puymirat, E, Jones, WS, Shah, BR, Sherwood, MW, Stringfellow, K, Sujjavanich, D, Toma, M, Van Diepen, SFP, Wilson, MD, Yan, AT-K, Lopes, RD, Trotter, C, Schiavi, LB, Garrido, M, Alvarisqueta, AF, Sassone, SA, Bordonava, AP, Alves De Lima, AE, Schmidberg, JM, Duronto, EA, Caruso, OC, Novaretto, LP, Angel Hominal, M, Montana, OR, Caccavo, A, Gomez Vilamajo, OA, Lorenzatti, AJ, Cartasegna, LR, Paterlini, GA, Mackinnon, IJ, Caime, GD, Amuchastegui, M, Salomone, R, Codutti, OR, Jure, HO, Bono, JOE, Hrabar, AD, Vallejos, JA, Ahuad Guerrero, RA, Novoa, F, Patocchi, CA, Zaidman, CJ, Giuliano, ME, Dran, RD, Vico, ML, Carnero, GS, Guzman, PN, Medrano Allende, JC, Garcia Brasca, DF, Bustamante Labarta, MH, Nani, S, Blumberg, EDS, Colombo, HR, Liberman, A, Luciardi, HL, Waisman, GD, Berli, MA, Duran, ROG, Cestari, HG, Luquez, HA, Giordano, JA, Saavedra, SS, Zapata, G, Costamagna, O, Llois, S, Waites, JH, Collins, N, Soward, A, Hii, CLS, Shaw, J, Arstall, MA, Horowitz, J, Rogers, JF, Colquhoun, D, Oqueli Flores, RE, Roberts-Thomson, P, Raffel, O, Lehman, SJ, Aroney, C, Coverdale, SGM, Garrahy, PJ, Starmer, G, Sader, M, Carroll, PA, Dick, R, Zweiker, R, Hoppe, U, Huber, K, Berger, R, Weidinger, F, Faes, D, Hermans, K, Pirenne, B, Leone, A, Hoffer, E, Vrolix, MCM, De Wolf, L, Wollaert, B, Castadot, M, Dujardin, K, Beauloye, C, Vervoort, G, Striekwold, H, Convens, C, Roosen, J, Barbato, E, Claeys, M, Cools, F, Terzic, I, Barakovic, F, Midzic, Z, Pojskic, B, Fazlibegovic, E, Durak-Nalbantic, A, Vulic, D, Muslibegovic, A, Goronja, B, Reis, G, Sousa, L, Nicolau, JC, Giorgeto, FE, Silva, RP, Maia, LN, Rech, R, Rossi, PRF, Cerqueira, MJAG, Duda, N, Kalil, R, Kormann, A, Abrantes, JAM, Pimentel Filho, P, Soggia, AP, De Santos, MON, Neuenschwander, F, Bodanese, LC, Michalaros, YL, Eliaschewitz, FG, Vidotti, MH, Leaes, PE, Botelho, RV, Kaiser, S, Fernandes Manenti, ERF, Precoma, DB, Moura Jorge, JC, Silva, PGMDB, Silveira, JA, Saporito, W, Marin Neto, JA, Feitosa, GS, Ritt, LEF, De Souza, JA, Costa, F, Souza, WKSB, Reis, HJL, Machado, L, Aidar Ayoub, JC, Todorov, GV, Nikolov, FP, Velcheva, ES, Tzekova, ML, Benov, HO, Petranov, SL, Tumbev, HS, Shehova-Yankova, NS, Markov, DT, Raev, DH, Mollov, MN, Kichukov, KN, Ilieva-Pandeva, KA, Ivanova, R, Mincheva, VM, Lazov, PV, Dimov, BI, Senaratne, M, Stone, J, Kornder, J, Pearce, S, Dion, D, Savard, D, Pesant, Y, Pandey, A, Robinson, S, Gosselin, G, Vizel, S, Hoag, G, Bourgeois, R, Morisset, A, Sabbah, E, Sussex, B, Kouz, S, MacDonald, P, Diaz, A, Michaud, N, Fell, D, Leung, R, Vuurmans, T, Lai, C, Nigro, F, Davies, R, Nogareda, G, Vijayaraghavan, R, Ducas, J, Lepage, S, Mehta, S, Cha, J, Dupuis, R, Fong, P, Rodes-Cabau, J, Fadlallah, H, Cleveland, D, Thao, H, Bata, I, Hameed, A, Pincetti, C, Potthoff, S, Prieto, JC, Acevedo, M, Aguirre, A, Vejar, M, Yanez, M, Araneda, G, Fernandez, M, Perez, L, Varleta, P, Florenzano, F, Huidobro, L, Raffo, CA, Olivares, C, Nahuelpan, L, Montecinos, H, Chen, J, Dong, Y, Huang, W, Wang, J, Huang, S, Yao, Z, Li, X, Cui, L, Lin, W, Sun, Y, Li, J, Zhang, X, Zhu, H, Chen, D, Huang, L, Dong, S, Su, G, Xu, B, Su, X, Cheng, X, Lin, J, Zong, W, Li, H, Feng, Y, Xu, D, Yang, X, Ke, Y, Lin, X, Zhang, Z, Zheng, Z, Luo, Z, Chen, Y, Ding, C, Zheng, Y, Peng, D, Li, Y, Wei, M, Liu, S, Yu, Y, Qu, B, Jiang, W, Zhou, Y, Zhao, X, Yuan, Z, Guo, Y, Xu, X, Shi, X, Ge, J, Fu, G, Bai, F, Fang, W, Shou, X, Lu, Q, Zhang, R, Zhu, J, Xu, Y, Fan, Z, Li, T, Wu, C, Jaramillo, N, Vallejo, GS, Botia, DCL, Lopez, RB, De Salazar, DIM, Bonfanti, AJC, Higuera, JD, Silva, SIB, Lozada, HJG, Arroyo, JAC, Mendoza, JLA, Ruiz, RLF, Jatin, FGM, Herazo, AS, Parada, JC, Triana, MAU, Strozzi, M, Car, S, Milicic, D, Bencic, ML, Pintaric, H, Prvulovic, D, Sikic, J, Persic, V, Mileta, D, Stambuk, K, Zdravko, B, Tomulic, V, Krstulovic, SM, Starcevic, B, Spinar, J, Horak, D, Stasek, J, Alan, D, Machova, V, Linhart, A, Novotny, V, Kaucak, V, Rokyta, R, Naplava, R, Coufal, Z, Adamkova, V, Podpera, I, Zizka, J, Motovska, Z, Marusincova, I, Svab, P, Heinc, P, Kuchar, J, Povolny, P, Matuska, J, Raungaard, B, Clemmensen, P, Bang, LE, May, O, Bottcher, M, Hove, JD, Frost, L, Gislason, G, Larsen, J, Johansen, PB, Hald, F, Jeppesen, J, Nielsen, T, Kristensen, KS, Walichiewicz, PM, Lomholdt, JD, Klausen, IC, Nielsen, PK, Davidsen, F, Videbaek, L, Soots, M, Vahula, V, Hedman, A, Soopold, U, Martsin, K, Kristjan, A, Taskinen, M-R, Porthan, K, Airaksinen, JK, Juonala, M, Kiviniemi, T, Vikman, S, Posio, P, Taurio, J, Huikuri, H, Kaikkonen, K, Coste, P, Ferrari, E, Morel, O, Montalescot, G, Barone-Rochette, G, Mansourati, J, Cottin, Y, Leclercq, F, Belhassane, A, Delarche, N, Boccara, F, Paganelli, F, Clerc, J, Schiele, F, Aboyans, V, Probst, V, Berland, J, Lefevre, T, Citron, B, Khintibidze, I, Shaburishvili, T, Pagava, Z, Ghlonti, R, Lominadze, Z, Khabeishvili, G, Hemetsberger, R, Rauch-Kroehnert, U, Stratmann, M, Appel, K-F, Schmidt, E, Omran, H, Stellbrink, C, Dorsel, T, Lianopoulos, E, Marx, R, Zirlik, A, Schellenberg, D, Heitzer, T, Laufs, U, Gielen, S, Winkelmann, B, Behrens, S, Sydow, K, Simonis, G, Muenzel, T, Werner, N, Leggewie, S, Boecker, D, Braun-Dullaeus, R, Toursarkissian, N, Jeserich, M, Weissbrodt, M, Schaeufele, T, Weil, J, Voeller, H, Waltenberger, J, Natour, M, Schmitt, S, Steiner, S, Heidenreich, L, Gremmler, U, Killat, H, Rieker, W, Patsilinakos, S, Kartalis, A, Manolis, A, Sionis, D, Skoumas, I, Athyros, V, Vardas, P, Parthenakis, F, Alexopoulos, D, Hahalis, G, Lekakis, J, Hatzitolios, A, Ovando, SRF, Benecke, JLA, De Leon, ERR, Yan, BPY, Siu, DCW, Turi, T, Merkely, B, Ungi, I, Lupkovics, G, Nagy, L, Katona, A, Edes, I, Muller, G, Horvath, I, Kapin, T, Falukozy, J, Kumbla, M, Sandhu, M, Annam, S, Proddutur, NR, Premchand, RK, Mahajan, A, Abhyanakar, AD, Kerkar, P, Govinda, RA, Oomman, A, Sinha, D, Patil, SN, Kahali, D, Sawhney, J, Joshi, AB, Chaudhary, S, Harkut, P, Guha, S, Porwal, S, Jujjuru, S, Pothineni, RB, Monteiro, MR, Khan, A, Iyengar, SS, Grewal, JS, Chopda, M, Fulwani, MC, Patange, A, Chopra, VK, Goyal, NK, Shinde, R, Manakshe, GV, Patki, N, Sethi, S, Munusamy, V, Karna, S, Adhyapak, S, Pandurangi, U, Mathur, R, Kalashetti, S, Bhagwat, A, Raghuraman, B, Yerra, SK, Bhansali, P, Borse, R, Das, S, Abdullakutty, J, Saathe, S, Palimkar, P, Abdullkutty, J, Sathe, S, Atar, S, Shechter, M, Mosseri, M, Arbel, Y, Lotan, C, Rosenschein, U, Katz, A, Henkin, Y, Francis, A, Klutstein, M, Nikolsky, E, Turgeman, Y, Halabi, M, Kornowski, R, Jonas, M, Amir, O, Rozenman, Y, Fuchs, S, Hussein, O, Gavish, D, Vered, Z, Caraco, Y, Elias, M, Tov, N, Lishner, M, Elias, N, Piovaccari, G, De Pellegrin, A, Guardigli, G, Licciardello, G, Auguadro, C, Cuccia, C, Salvioni, A, Musumeci, G, Calabro, P, Novo, S, Faggiano, P, De Cesare, NB, Berti, S, Cavallini, C, Puccioni, E, Galvani, M, Tespili, M, Piatti, P, Palvarini, M, De Luca, G, Violini, R, De Leo, A, Filardi, PP, Ferratini, M, Ricca, V, Dai, K, Kamiya, H, Ando, K, Takeda, Y, Morino, Y, Hata, Y, Kimura, K, Kishi, K, Michishita, I, Uehara, H, Higashikata, T, Hirayama, A, Hirooka, K, Sakagami, S, Taguchi, S, Koike, A, Fujinaga, H, Koba, S, Kozuma, K, Kawasaki, T, Ono, Y, Shimizu, M, Katsuda, Y, Wada, A, Shinke, T, Ako, J, Fujii, K, Takahashi, T, Sakamoto, T, Furukawa, Y, Sugino, H, Mano, T, Utsu, N, Ito, K, Haraguchi, T, Ueda, Y, Nishibe, A, Fujimoto, K, Masutani, M, Yoon, JH, Park, HS, Chae, I-H, Kim, MH, Jeong, MH, Rha, S, Kim, C, Kim, H-S, Hong, T, Tahk, S-J, Kim, Y, Busmane, A, Pontaga, N, Strelnieks, A, Mintale, I, Sime, I, Petrulioniene, Z, Kavaliauskiene, R, Jurgaitiene, R, Sakalyte, G, Slapikas, R, Norkiene, S, Misonis, N, Kibarskis, A, Kubilius, R, Bojovski, S, Lozance, N, Kjovkaroski, A, Doncovska, S, Ong, TK, Kasim, S, Maskon, O, Kandasamy, B, Liew, HB, Mohamed, WMIW, Garcia Castillo, A, Carrillo Calvillo, J, Fajardo Campos, P, Nunez Fragoso, JC, Bayram Llamas, EA, Alcocer Gamba, MA, Carranza Madrigal, J, Gonzalez Salas, LG, Lopez Rosas, E, Gonzalez Diaz, B, Salcido Vazquez, E, Nacoud Ackar, A, Llamas Esperon, GA, Martinez Sanchez, CR, Guerrero De Leon, M, Suarez Otero, R, Fanghanel Salmon, G, Perez Rios, JA, Garza Ruiz, JA, Breedveld, RW, Hoogslag, PAM, Suryapranata, H, Oomen, A, Wiersma, JJ, Van Der Wal, RMA, Van Huysduynen-Monraats, PSH, Karalis, I, Verdel, GJE, Brueren, BRG, Troquay, RP, Viergever, EP, Al-Windy, NYY, Bartels, GL, Cornel, JH, Hermans, WRM, Herrman, JPR, Bos, RJ, Groutars, RGEJ, Van Der Zwaan, CC, Kaplan, R, Ronner, E, Groenemeijer, BE, Bronzwaer, PNA, Liem, AAH, Rensing, BJWM, Bokern, MJJA, Nijmeijer, R, Hersbach, FMRJ, Willems, FF, Gosselink, ATM, Elliott, J, Wilkins, G, Fisher, R, Scott, D, Hart, H, Stewart, R, Harding, S, Ternouth, I, Fisher, N, Aitken, D, Anscombe, R, Davidson, L, Tomala, T, Nygard, O, Sparby, JA, Andersen, K, Gullestad, L, Jortveit, J, Munk, PS, Singsaas, EG, Hurtig, U, Calderon Ticona, JR, Durand Velasquez, JR, Negron Miguel, SA, Sanabria Perez, ES, Carrion Chambilla, JM, Chavez Ayala, CA, Castillo Leon, RP, Vargas Gonzales, RJ, Hernandez Zuniga, JD, Camacho Cosavalente, LA, Bravo Mannucci, JE, Heredia Landeo, J, Llerena Navarro, NC, Roldan Concha, YM, Rodriguez Chavez, V-CE, Anchante Hernandez, HA, Zea Nunez, CA, Mogrovejo Ramos, W, Ferrolino, A, Sy, RAG, Tirador, L, Matiga, G, Coching, RM, Bernan, A, Rogelio, G, Morales, DD, Tan, E, Sulit, DJ, Wlodarczak, A, Jaworska, K, Skonieczny, G, Pawlowicz, L, Wojewod, P, Busz-Papiez, B, Bednarski, J, Goch, A, Staneta, P, Dulak, E, Saminsk, K, Krasowski, W, Sudnik, W, Zurakowski, A, Skorski, M, Lysek, R, Miklaszewicz, B, Kubica, J, Lipko, JA, Kostarska-Srokosz, E, Piepiorka, M, Drzewiecka, A, Sciborski, R, Stasiewski, A, Blicharski, T, Bystryk, L, Szpajer, M, Korol, M, Czerski, T, Mirek-Bryniarska, E, Gniot, J, Lubinski, A, Gorny, J, Franek, E, Raczak, G, Szwed, H, Monteiro, P, Bastos, JM, Pereira, HH, Martins, D, Seixo, F, Mendonca, C, Botelho, A, Minescu, B, Istratoaie, O, Tesloianu, DN, Cristian, G, Podoleanu, CGC, Constantinescu, MCA, Bengus, CM, Militaru, C, Rosu, D, Parepa, IR, Matei, AV, Alexandru, TM, Coman, I, Cioranu, RS, Dimulescu, D, Shvarts, Y, Orlikova, O, Kobalava, Z, Barbarash, OL, Markov, V, Lyamina, N, Gordienko, A, Zrazhevsky, K, Vishnevsky, AY, Gurevich, V, Stryuk, R, Lomakin, NV, Bokarev, I, Shalaev, S, Khaisheva, L, Chizhov, P, Viktorova, I, Osokina, N, Akatova, E, Chumakova, G, Libov, I, Voevoda, MI, Tretyakova, TV, Baranov, E, Shustov, S, Yakushin, S, Gordeev, I, Khasanov, N, Reshetko, O, Sotnikova, T, Molchanova, O, Nikolaev, K, Gapon, L, Baranova, E, Shogenov, Z, Kosmachova, E, Povzun, A, Egorova, L, Tyrenko, VV, Ivanov, IG, Kanorsky, S, Simic, D, Ivanovic, N, Davidovic, G, Tasic, N, Asanin, MR, Stojic, S, Apostolovic, SR, Ilic, S, Putnikovic, B, Stankovic, A, Arandjelovic, A, Radovanovic, S, Balinovac, J, Dincic, DV, Seferovic, P, Dodic, S, Dimkovic, S, Poh, K-K, Ong, HY, Micko, K, Nociar, J, Pella, D, Fulop, P, Hranai, M, Palka, J, Mazur, J, Majercak, I, Dzupina, A, Fazekas, F, Gonsorcik, J, Bugan, V, Selecky, J, Kamensky, G, Strbova, J, Smik, R, Dukat, A, Olexa, P, Zuran, I, Poklukar, J, Suligoj, NC, Cevc, M, Cyster, HP, Ranjith, N, Corbett, C, Bayat, J, Makotoko, EM, Kapp, IE, Basson, MMDV, Lottering, H, Van Zyl, LJ, Sebastian, PJ, Pillay, T, Saaiman, JA, Commerford, PJ, Cassimjee, S, Ebrahim, IO, Sarvan, M, Mynhardt, JH, Reuter, H, Moodley, R, Vida, M, Cequier Fillat, AR, Peris, VB, Jimenez, FF, Marin, F, Cruz Fernandez, JM, Gil-Extremera, B, Diz, FW, Garcia-Dorado, D, Iniguez, A, Tunon Fernandez, J, Gonzalez-Juanatey, JR, Fernandez Portales, J, Civeira Murillo, F, Matas Pericas, L, Luis Zamorano, J, De Mora Martin, M, Bruguera Cortada, J, Alonso Martin, JJ, De Berrazueta Fernandez, JR, Diaz Fernandez, JF, Garcia Lledo, JA, Cosin Sales, J, Botas Rodriguez, J, Gusi Tragant, G, Benedicto, A, Gonzalez-Juanatey, C, Camprubi Potau, M, Plaza Perez, I, Moris De La Tassa, C, Loma-Osorio Rincon, P, Balaguer Recena, J, Escudier, JM, Coca Payeras, A, Alonso Orcajo, N, Valdivielso, P, Constantine, G, Haniffa, R, Tissera, N, Amarasekera, S, Fernando, N, Jayawardena, J, Santharaj, W, Ekanayaka, R, Mendis, S, Senaratne, V, Mayurathan, G, Sirisena, T, Rajapaksha, A, Herath, JI, Amarasena, N, Berglund, S, Rasmanis, G, Witt, N, Mourtzinis, G, Nicol, P, Hansen, O, Romeo, S, Jensen, SA, Torstensson, I, Ahremark, U, Sundelin, T, Moccetti, T, Mach, F, Binder, R, Tsai, W-C, Ueng, K-C, Lai, W-T, Liu, M-E, Hwang, J-J, Yin, W-H, Hsieh, I-C, Lin, WH, Kuo, J-Y, Huang, T-Y, Fang, C-Y, Kaewsuwanna, P, Soonfuang, W, Jintapakorn, W, Sukonthasarn, A, Wongpraparut, N, Sastravaha, K, Sansanayudh, N, Kehasukcharoen, W, Piyayotai, D, Chotnoparatpat, P, Camsari, A, Kultursay, H, Mutlu, B, Ersanli, M, Demirtas, M, Kirma, C, Ural, E, Koldas, L, Karpenko, O, Prokhorov, A, Vakaluyk, I, Myshanych, H, Reshotko, D, Batushkin, V, Rudenko, L, Kovalskyi, I, Kushnir, M, Tseluyko, V, Mostovoy, Y, Stanislavchuk, M, Kyiak, Y, Karpenko, Y, Malynovsky, Y, Klantsa, A, Kutniy, O, Amosova, E, Tashchuk, V, Leshchuk, O, Rishko, M, Kopytsya, M, Yagensky, A, Vatutin, M, Bagriy, A, Barna, OM, Ushakov, O, Dzyak, G, Goloborodko, B, Rudenko, A, Zheleznyy, V, Trevelyan, J, Zaman, A, Lee, K, Moriarty, A, Aggarwal, RK, Clifford, P, Wong, Y-K, Iqbal, SMR, Subkovas, E, Braganza, D, Sarkar, D, Storey, R, Griffiths, H, Mcclure, S, Muthusamy, R, Kurian, J, Levy, T, Barr, C, Kadr, H, Gerber, R, Simaitis, A, Soran, H, Mathur, A, Brodison, A, Oliver, R, Mudawi, T, Reynolds, T, Sharman, D, Butler, R, Wilkinson, P, Lip, GYH, Halcox, J, Vardi, G, Baldari, D, Brabham, D, Treasure, C, Dahl, C, Palmer, B, Wiseman, A, Puri, S, Mohart, AE, Ince, C, Flores, E, Wright, S, Cheng, S-C, Rosenberg, M, Rogers, W, Kosinski, E, Forgosh, L, Waltman, J, Khan, M, Shoukfeh, M, Dagher, G, Lieber, I, Kumar, P, East, C, Krichmar, P, White, L, Knickelbine, T, Haldis, T, Gillespie, E, Suh, D, Arif, I, Akhter, F, Carlson, E, D'Urso, M, El-Ahdab, F, Nelson, W, Harris, B, Cohen, S, Carter, L, Sabatino, K, Haddad, T, Malik, A, Rao, S, Mulkay, A, Jovin, I, Klancke, K, Malhotra, V, Devarapalli, SK, Koren, M, Chandna, H, Dodds, G, Janik, M, Moran, J, Sumner, A, Kobayashi, J, Davis, W, Yazdani, S, Pasquini, J, Thakkar, M, Vedere, A, Leimbach, W, Rider, J, Singh, N, Shah, AV, Janosik, D, Pepine, C, Berman, B, Gelormini, J, Daniels, C, Keating, F, Kondo, NI, Shetty, S, Waider, W, Takata, T, Abu-Fadel, M, Shah, V, Aggarwal, R, Izzo, M, Kumar, A, Hattler, B, Link, C, Bortnick, A, Kinzfogl, G, Ghitis, A, Larry, J, Teufel, E, Kuhlman, P, Mclaurin, B, Zhang, W, Thew, S, Abbas, J, White, M, Ranadive, N, Gring, C, Henderson, D, Schuchard, T, Farhat, N, Kline, G, Mahal, S, Whitaker, J, Speirs, S, Andersen, R, Daboul, N, Horwitz, P, Ponce, G, Jafar, Z, Mcgarvey, J, Panchal, V, Voyce, S, Blok, T, Sheldon, W, Azizad, MM, Schmalfuss, C, Picone, M, Herzog, W, Lindsey, J, Nowins, R, Lepor, N, El Shahawy, M, Weintraub, H, Irimpen, A, May, W, Galski, T, Chu, A, Mody, F, Hodes, Z, Rose, G, Fairlamb, J, Lambert, C, Raisinghani, A, Abbate, A, King, M, Carey, C, Gerber, J, Younis, L, Park, HT, Vidovich, M, Knutson, T, Friedman, D, Chaleff, F, Loussararian, A, Rozeman, P, Kimmelstiel, C, Silver, K, Foster, M, Tonnessen, G, Amlani, M, Wali, A, Malozzi, C, Wattanakit, K, O'Donnell, PJ, Singal, D, Jaffrani, N, Banuru, S, Fisher, D, Xenakis, M, Perlmutter, N, Bhagwat, R, Strader, J, Akyea-Djamson, A, Labroo, A, Marais, HJ, Claxton, E, Berk, M, Rossi, P, Joshi, P, Khaira, AS, Kumkumian, G, Lupovitch, S, Purow, J, Welka, S, Hoffman, D, Fischer, S, Soroka, E, Eagerton, D, Pancholy, S, Ray, M, Farrar, M, Pollock, S, French, WJ, Diamantis, S, Gimple, L, Neustel, M, Schwartz, S, Pereira, E, Spriggs, D, Strain, J, Vo, A, Chane, M, Hall, J, Vijay, N, Lotun, K, Lester, FM, Nahhas, A, Pope, T, Nager, P, Vohra, R, Bashir, R, Ahmed, H, Berlowitz, M, Fishberg, R, Barrucco, R, Yang, E, Radin, M, Sporn, D, Eisenberg, S, Landzberg, J, Mcgough, M, Turk, S, Schwartz, M, Sundram, PS, Jain, D, Zainea, M, Bayron, C, Karlsberg, R, Lui, H, Keen, W, Westerhausen, D, Khurana, S, Agarwal, H, Birchem, J, Penny, W, Chang, M, Murphy, S, Schifferdecker, B, Gilbert, JM, Chalavarya, G, Eaton, C, Schmedtje, JF, Christenson, S, Denham, D, Macdonell, A, Gibson, P, Rahman, A, Al Joundi, T, Conrad, G, Kotha, P, Love, M, Giesler, G, Rubenstein, H, Akright, L, Krawczyk, J, Wells, T, Welker, J, Foster, R, Gilmore, R, Anderson, J, Jacoby, D, Gardner, G, Dandillaya, R, Vora, K, Kostis, J, Hunter, J, Laxson, D, Ball, E, Camp, A, Lopes, R, Egydio, F, Kawakami, A, Oliveira, J, Wozniak, J, Matthews, A, Ratky, C, Valiris, J, Berdan, L, Hepditch, A, Quintero, K, Rorick, T, Westbrook, M, Pascual, A, Rovito, C, Bezault, M, Drouet, E, Simon, T, Alsweiler, C, Luyten, A, Aylward, P, Butters, J, Griffith, L, Shaw, M, Grunberg, L, Islam, S, Bougon, N, Faustino, D, Fontecave, S, Murphy, J, Verrier, M, Agnetti, V, Andersen, D, Badreddine, E, Bekkouche, M, Bouancheau, C, Brigui, I, Brocklehurst, M, Cianciarulo, J, Devaul, D, Domokos, S, Gache, C, Gobillot, C, Guillou, S, Healy, J, Heath, M, Jaiwal, G, Javierre, C, Labeirie, J, Monier, M, Morales, U, Mrabti, A, Mthombeni, B, Okan, B, Smith, L, Sheller, J, Sopena, S, Pellan, V, Benbernou, F, Bengrait, N, Lamoureux, M, Kralova, K, Scemama, M, Bejuit, R, Coulange, A, Berthou, C, Repincay, J, Lorenzato, C, Etienne, A, Gouet, V, Loizeau, V, Normand, M, Ourliac, A, Rondel, C, Adamo, A, Beltran, P, Barraud, P, Dubois-Gache, H, Halle, B, Metwally, L, Mourgues, M, Sotty, M, Vincendet, M, Cotruta, R, Zhu, C, Fournie-Lloret, D, Morrello, C, Perthuis, A, Picault, P, Zobouyan, I, ODYSSEY OUTCOMES Comm, İÜC, Ege Üniversitesi, Rushton-Smith, Sophie, and ODYSSEY OUTCOMES Committees and Investigators
Subjects: Male, Cardiac & Cardiovascular Systems, MONOCLONAL-ANTIBODY, alirocumab, Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage, law.invention, PCSK9, chemistry.chemical_compound, Randomized controlled trial, law, Cardiac and Cardiovascular Systems, 1102 Cardiorespiratory Medicine and Haematology, Hypercholesterolemia/blood, Kardiologi, Hazard ratio, Middle Aged, Treatment Outcome, SAFETY, Cardiology, Female, Drug Therapy, Combination, Cholesterol, LDL/antagonists & inhibitors, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, REDUCING LIPIDS, Akutes Koronarsyndrom, acute coronary syndrome, cholesterol, mortality, PCSK9 protein, Antibodies, Monoclonal, Humanized/administration & dosage, medicine.medical_specialty, Acute coronary syndrome, Injections, Subcutaneous, Hypercholesterolemia, Placebo, Antibodies, Monoclonal, Humanized, 1117 Public Health and Health Services, Sterblichkeit, Double-Blind Method, Physiology (medical), Internal medicine, medicine, Humans, ddc:610, Alirocumab, Aged, Science & Technology, Cholesterol, business.industry, EVOLOCUMAB, 1103 Clinical Sciences, Cholesterol, LDL, medicine.disease, EFFICACY, Increased risk, chemistry, Peripheral Vascular Disease, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, Acute Coronary Syndrome/blood, Cholesterin, Human medicine, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Follow-Up Studies
Abstract: bastos, jose/0000-0002-9526-3123; Manakshe, Gajendra/0000-0002-4983-4271; Tse, Hung Fat/0000-0002-9578-7808; Gislason, Gunnar H/0000-0002-0548-402X; Taskinen, Marja-Riitta/0000-0002-6229-3588; Racca, Vittorio/0000-0002-4465-3789; Keskin, Kudret/0000-0002-9049-1530; Sherwood, Matthew/0000-0002-4305-5883; Sandhu, Manjinder/0000-0003-2538-2079; Nikolaev, Konstantin/0000-0003-4601-6203; Ersanli, Murat/0000-0003-1847-3087; Raffel, Owen C/0000-0001-5470-7050; Abbate, Antonio/0000-0002-1930-785X; Muenzel, Thomas/0000-0001-5503-4150; Leonardi, Sergio/0000-0002-4800-6132; Chumakova, Galina A/0000-0002-2810-6531; Podoleanu, Cristian/0000-0001-9987-2519; Pereira, Helder/0000-0001-8656-4883; Reshetko, Olga/0000-0003-3107-7636, WOS: 000476768100007, PubMed: 31117810, Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. in a prespecified analysis of 8242 patients eligible for >= 3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P= 100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; P-interaction=0.007). in the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for >= 3 years, if baseline LDL-C is >= 100 mg/dL, or if achieved LDL-C is low., Sanofi; Regeneron Pharmaceuticals, Inc., The trial was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Published: 2019

35. Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Author: Patel, RS, Schmidt, AF, Tragante, V, McCubrey, RO, Holmes, MV, Howe, LJ, Direk, K, Åkerblom, A, Leander, K, Virani, SS, Kaminski, KA, Muehlschlegel, JD, Dubé, M-P, Allayee, H, Almgren, P, Alver, M, Baranova, EV, Behlouli, H, Boeckx, B, Braund, PS, Breitling, LP, Delgado, G, Duarte, NE, Dufresne, L, Eriksson, N, Foco, L, Gijsberts, CM, Gong, Y, Hartiala, J, Heydarpour, M, Hubacek, JA, Kleber, M, Kofink, D, Kuukasjärvi, P, Lee, V-V, Leiherer, A, Lenzini, PA, Levin, D, Lyytikäinen, L-P, Martinelli, N, Mons, U, Nelson, CP, Nikus, K, Pilbrow, AP, Ploski, R, Sun, YV, Tanck, MWT, Tang, WHW, Trompet, S, Van Der Laan, SW, Van Setten, J, Vilmundarson, RO, Anselmi, C, Vlachopoulou, E, Boerwinkle, E, Briguori, C, Carlquist, JF, Carruthers, KF, Casu, G, Deanfield, J, Deloukas, P, Dudbridge, F, Fitzpatrick, N, Gigante, B, James, S, Lokki, M-L, Lotufo, PA, Marziliano, N, Mordi, IR, Muhlestein, JB, Newton-Cheh, C, Pitha, J, Saely, CH, Samman-Tahhan, A, Sandesara, PB, Teren, A, Timmis, A, Van De Werf, F, Wauters, E, Wilde, AAM, Ford, I, Stott, DJ, Algra, A, Andreassi, MG, Ardissino, D, Arsenault, BJ, Ballantyne, CM, Bergmeijer, TO, Bezzina, CR, Body, SC, Bogaty, P, De Borst, GJ, Brenner, H, Burkhardt, R, Carpeggiani, C, Condorelli, G, Cooper-Dehoff, RM, Cresci, S, De Faire, U, Doughty, RN, Drexel, H, Engert, JC, Fox, KAA, Girelli, D, Hagström, E, Hazen, SL, Held, C, Hemingway, H, Hoefer, IE, Hovingh, GK, Johnson, JA, De Jong, PA, Jukema, JW, Kaczor, MP, Kähönen, M, Kettner, J, Kiliszek, M, Klungel, OH, Lagerqvist, B, Lambrechts, D, Laurikka, JO, Lehtimäki, T, Lindholm, D, Mahmoodi, BK, Der Zee, AH, McPherson, R, Melander, O, Metspalu, A, Pepinski, W, Olivieri, O, Opolski, G, Palmer, CN, Pasterkamp, G, Pepine, CJ, Pereira, AC, Pilote, L, Quyyumi, AA, Richards, AM, Sanak, M, Scholz, M, Siegbahn, A, Sinisalo, J, Smith, JG, Spertus, JA, Stewart, AFR, Szczeklik, W, Szpakowicz, A, Berg, JM, Thanassoulis, G, Thiery, J, Van Der Graaf, Y, Visseren, FLJ, Waltenberger, J, Van Der Harst, P, Tardif, J-C, Sattar, N, Lang, CC, Paré, G, Brophy, JM, Anderson, JL, März, W, Wallentin, L, Cameron, VA, Horne, BD, Samani, NJ, Hingorani, AD, and Asselbergs, FW
Subjects: Male, Myocardial Infarction, genetic risk factor, Coronary Artery Disease, Middle Aged, Article, chromosome 9p21, Gene Frequency, Risk Factors, Case-Control Studies, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, cardiovascular diseases, Chromosomes, Human, Pair 9, secondary prevention
Abstract: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
Published: 2019

36. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

Author: Ray KK, Colhoun HM, Szarek M, Baccara-Dinet M, Bhatt DL, Bittner VA, Budaj AJ, Diaz R, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Loizeau V, Lopes RD, Moryusef A, Murin J, Pordy R, Ristic AD, Roe MT, Tuñón J, White HD, Zeiher AM, Schwartz GG, Steg PG, ODYSSEY OUTCOMES Committees and Investigators, and Lovric Bencic, M.
Subjects: diabetes mellitus, alirocuma, acute coronary syndrome outcomes
Abstract: ODYSSEY OUTCOMES was a randomised, double-blind, placebo- controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1–12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks ; randomisation was stratified by country and was done centrally with an interactive voice- response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65–1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)—defined on the basis of patient history, review of medical records, or baseline HbA1cor fasting serum glucose—and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.
Published: 2019

37. Alirocumab Reduces Total Hospitalizations and Increases Days Alive and Out of Hospital in the ODYSSEY OUTCOMES Trial

Author: DiCenso, D, Gotcheva, N, Sourdille, T, White, HD, Schwartz, GG, Steg, PG, Bhatt, DL, Bittner, VA, Diaz, R, Harrington, RA, Jukema, JW, Szarek, M, Zeiher, AM, Tricoci, P, Mahaffey, KW, Edelberg, JM, Hanotin, C, Lecorps, G, Moryusef, A, Pordy, R, Sasiela, WJ, Drexel, H, Sinnaeve, P, Dilic, M, Gotcheva, NN, Goodman, SG, Prieto, JC, Yong, H, Lopez-Jaramillo, P, Pecin, I, Reiner, Z, Poulsen, SH, Viigimaa, M, Nieminen, MS, Danchin, N, Chumburidze, V, Tse, HF, Xavier, D, Zahger, D, Valgimigli, M, Kim, HS, Erglis, A, Laucevicius, A, Lopez, R, Lopez, GAR, Alings, M, Chua, T, Murin, J, Fras, Z, Dalby, AJ, Tunon, J, De Silva, HA, Chiang, CE, Sritara, P, Guneri, S, Parkhomenko, A, Ray, KK, Moriarty, PM, Roe, MT, Chaitman, B, Kelsey, SF, Olsson, AG, Rouleau, JL, Simoons, ML, Alexander, K, Meloni, C, Rosenson, R, Sijbrands, EJG, Alexander, JH, Armaganijan, L, Bagai, A, Bahit, MC, Brennan, JM, Clifton, S, DeVore, AD, Deloatch, S, Dickey, S, Dombrowski, K, Ducrocq, G, Eapen, Z, Endsley, P, Eppinger, A, Harrison, RW, Hess, CN, Hlatky, MA, Jordan, JD, Knowles, JW, Kolls, BJ, Kong, DF, Leonardi, S, Lillis, L, Maron, DJ, Marcus, J, Mathews, R, Mehta, RH, Mentz, RJ, Moreira, HG, Patel, CB, Pereira, SB, Perkins, L, Povsic, TJ, Puymirat, E, Jones, WS, Shah, BR, Sherwood, MW, Stringfellow, K, Sujjavanich, D, Toma, M, Van Diepen, SFP, Wilson, MD, Yan, ATK, Lopes, RD, Trotter, C, Schiavi, LB, Garrido, M, Alvarisqueta, AF, Sassone, SA, Bordonava, AP, De Lima, AEA, Schmidberg, JM, Duronto, EA, Caruso, OC, Novaretto, LP, Hominal, MA, Montana, OR, Caccavo, A, Vilamajo, OAG, Lorenzatti, AJ, Cartasegna, LR, Paterlini, GA, Mackinnon, IJ, Caime, GD, Amuchastegui, M, Salomone, R, Codutti, OR, Jure, HO, Bono, JOE, Hrabar, AD, Vallejos, JA, Guerrero, RAA, Novoa, F, Patocchi, CA, Zaidman, CJ, Giuliano, ME, Dran, RD, Vico, ML, Carnero, GS, Guzman, PN, Allende, JCM, Brasca, DFG, Labarta, MHB, Nani, S, Blumberg, EDS, Colombo, HR, Liberman, A, Luciardi, HL, Waisman, GD, Berli, MA, Duran, ROG, Cestari, HG, Luquez, HA, Giordano, JA, Saavedra, SS, Zapata, G, Costamagna, O, Llois, S, Waites, JH, Collins, N, Soward, A, Aylward, PE, Hii, CLS, Shaw, J, Arstall, MA, Horowitz, J, Rogers, JF, Colquhoun, D, Flores, REO, Roberts-Thomson, P, Raffel, O, Lehman, SJ, Aroney, C, Coverdale, SGM, Garrahy, PJ, Starmer, G, Sader, M, Carroll, PA, Dick, R, Zweiker, R, Hoppe, U, Huber, K, Berger, R, Weidinger, F, Faes, D, Hermans, K, Pirenne, B, Leone, A, Hoffer, E, Vrolix, MCM, De Wolf, L, Wollaert, B, Castadot, M, Dujardin, K, Beauloye, C, Vervoort, G, Striekwold, H, Convens, C, Roosen, J, Barbato, E, Claeys, M, Cools, F, Terzic, I, Barakovic, F, Midzic, Z, Pojskic, B, Fazlibegovic, E, Durak-Nalbantic, A, Vulic, D, Muslibegovic, A, Goronja, B, Reis, G, Sousa, L, Nicolau, JC, Giorgeto, FE, Silva, RP, Maia, LN, Rech, R, Rossi, PRF, Cerqueira, MJAG, Duda, N, Kalil, R, Kormann, A, Abrantes, JAM, Pimentel, P, Soggia, AP, de Santos, MON, Neuenschwander, F, Bodanese, LC, Michalaros, YL, Eliaschewitz, FG, Vidotti, MH, Leaes, PE, Botelho, RV, Kaiser, S, Manenti, ERFF, Precoma, DB, Jorge, JCM, Silva, PGMD, Silveira, JA, Saporito, W, Marin, JA, Feitosa, GS, Ritt, LEF, de Souza, JA, Costa, F, Souza, WKSB, Reis, HJL, Machado, L, Ayoub, JCA, Todorov, GV, Nikolov, FP, Velcheva, ES, Tzekova, ML, Benov, HO, Petranov, SL, Tumbev, HS, Shehova-Yankova, NS, Markov, DT, Raev, DH, Mollov, MN, Kichukov, KN, Ilieva-Pandeva, KA, Ivanova, R, Mincheva, VM, Lazov, PV, Dimov, BI, Senaratne, M, Stone, J, Kornder, J, Pearce, S, Dion, D, Savard, D, Pesant, Y, Pandey, A, Robinson, S, Gosselin, G, Vizel, S, Hoag, G, Bourgeois, R, Morisset, A, Sabbah, E, Sussex, B, Kouz, S, MacDonald, P, Diaz, A, Michaud, N, Fell, D, Leung, R, Vuurmans, T, Lai, C, Nigro, F, Davies, R, Nogareda, G, Vijayaraghavan, R, Ducas, J, Lepage, S, Mehta, S, Cha, J, Dupuis, R, Fong, P, Rodes-Cabau, J, Fadlallah, H, Cleveland, D, Huynh, T, Bata, I, Hameed, A, Pincetti, C, Potthoff, S, Acevedo, M, Aguirre, A, Vejar, M, Yanez, M, Araneda, G, Fernandez, M, Perez, L, Varleta, P, Florenzano, F, Huidobro, L, Raffo, CA, Olivares, C, Nahuelpan, L, Montecinos, H, Chen, JY, Dong, YG, Huang, WJ, Wang, JZ, Huang, SA, Yao, ZH, Li, X, Cui, L, Lin, WH, Sun, YM, Wang, JF, Li, JP, Zhang, XL, Zhu, H, Chen, D, Huang, L, Dong, SH, Su, GH, Xu, BA, Su, X, Cheng, XS, Lin, JX, Zong, WX, Li, HM, Feng, Y, Xu, DL, Yang, XC, Ke, YN, Lin, XF, Zhang, Z, Zheng, ZQ, Luo, ZR, Chen, YD, Ding, CH, Zheng, Y, Li, XD, Peng, DQ, Li, Y, Wei, M, Liu, SW, Yu, YH, Qu, BM, Jiang, WH, Zhou, YJ, Zhao, XS, Yuan, ZY, Guo, Y, Xu, XP, Shi, XB, Ge, JB, Fu, GS, Bai, F, Fang, WY, Shou, XL, Yang, XJ, Wang, JA, Sun, YX, Lu, QH, Zhang, RY, Zhu, JH, Xu, YZ, Fan, ZC, Li, TC, Wu, C, Jaramillo, N, Vallejo, GS, Botia, DCL, Lopez, RB, De Salazar, DIM, Bonfanti, AJC, Higuera, JD, Silva, SIB, Lozada, HJG, Arroyo, JAC, Mendoza, JLA, Ruiz, RLF, Jatin, FGM, Herazo, AS, Parada, JC, Triana, MAU, Strozzi, M, Car, S, Milicic, D, Bencic, ML, Pintaric, H, Prvulovic, D, Sikic, J, Persic, V, Mileta, D, Stambuk, K, Zdravko, B, Tomulic, V, Krstulovic, SM, Starcevic, B, Spinar, J, Horak, D, Stasek, J, Alan, D, Machova, V, Linhart, A, Novotny, V, Kaucak, V, Rokyta, R, Naplava, R, Coufal, Z, Adamkova, V, Podpera, I, Zizka, J, Motovska, Z, Marusincova, I, Svab, P, Ostadal, P, Heinc, P, Kuchar, J, Povolny, P, Matuska, J, Raungaard, B, Clemmensen, P, Bang, LE, May, O, Bottcher, M, Hove, JD, Frost, L, Gislason, G, Larsen, J, Johansen, PB, Hald, F, Jeppesen, J, Nielsen, T, Kristensen, KS, Walichiewicz, PM, Lomholdt, JD, Klausen, IC, Nielsen, PK, Davidsen, F, Videbaek, L, Soots, M, Vahula, V, Hedman, A, Soopold, U, Martsin, K, Kristjan, A, Taskinen, MR, Porthan, K, Airaksinen, JK, Juonala, M, Kiviniemi, T, Vikman, S, Posio, P, Taurio, J, Huikuri, H, Kaikkonen, K, Coste, P, Ferrari, E, Morel, O, Montalescot, G, Barone-Rochette, G, Mansourati, J, Cottin, Y, Leclercq, F, Belhassane, A, Delarche, N, Boccara, F, Paganelli, F, Clerc, J, Schiele, F, Aboyans, V, Probst, V, Berland, J, Lefevre, T, Citron, B, Khintibidze, I, Shaburishvili, T, Pagava, Z, Ghlonti, R, Lominadze, Z, Khabeishvili, G, Hemetsberger, R, Rauch-Krohnert, U, Stratmann, M, Appel, KF, Schmidt, E, Omran, H, Stellbrink, C, Dorsel, T, Lianopoulos, E, Marx, R, Zirlik, A, Schellenberg, D, Heitzer, T, Laufs, U, Marx, N, Gielen, S, Winkelmann, B, Behrens, S, Sydow, K, Simonis, G, Muenzel, T, Werner, N, Leggewie, S, Bocker, D, Braun-Dullaeus, R, Toursarkissian, N, Jeserich, M, Weissbrodt, M, Schaeufele, T, Weil, J, Voller, H, Waltenberger, J, Natour, M, Schmitt, S, Steiner, S, Heidenreich, L, Gremmler, U, Killat, H, Rieker, W, Patsilinakos, S, Kartalis, A, Manolis, A, Sionis, D, Liberopoulos, E, Skoumas, I, Athyros, V, Vardas, P, Parthenakis, F, Alexopoulos, D, Hahalis, G, Lekakis, J, Hatzitolios, A, Ovando, SRF, Valdovinos, PCM, Benecke, JLA, De Leon, ERR, Yan, BPY, Siu, DCW, Turi, T, Merkely, B, Kiss, RG, Ungi, I, Lupkovics, G, Nagy, L, Katona, A, Edes, I, Muller, G, Horvath, I, Kapin, T, Falukozy, J, Kumbla, M, Sandhu, M, Annam, S, Proddutur, NR, Premchand, RK, Mahajan, A, Abhyanakar, AD, Kerkar, P, Govinda, RA, Oomman, A, Sinha, D, Patil, SN, Kahali, D, Sawhney, J, Joshi, AB, Chaudhary, S, Harkut, P, Guha, S, Porwal, S, Jujjuru, S, Pothineni, RB, Monteiro, MR, Khan, A, Iyengar, SS, Grewal, JS, Chopda, M, Fulwani, MC, Patange, A, Chopra, VK, Goyal, NK, Shinde, R, Manakshe, GV, Patki, N, Sethi, S, Munusamy, V, Karna, S, Adhyapak, S, Pandurangi, U, Mathur, R, Kalashetti, S, Bhagwat, A, Raghuraman, B, Yerra, SK, Bhansali, P, Borse, R, Das, S, Abdullakutty, J, Saathe, S, Abdullkutty, J, Sathe, S, Palimkar, P, Atar, S, Shechter, M, Mosseri, M, Arbel, Y, Lotan, C, Rosenschein, U, Katz, A, Henkin, Y, Francis, A, Klutstein, M, Nikolsky, E, Turgeman, Y, Halabi, M, Kornowski, R, Jonas, M, Amir, O, Rozenman, Y, Fuchs, S, Hussein, O, Gavish, D, Vered, Z, Caraco, Y, Elias, M, Tov, N, Lishner, M, Elias, N, Piovaccari, G, De Pellegrin, A, Guardigli, G, Licciardello, G, Auguadro, C, Cuccia, C, Salvioni, A, Musumeci, G, Calabro, P, Novo, S, Faggiano, P, De Cesare, NB, Berti, S, Cavallini, C, Puccioni, E, Galvani, M, Tespili, M, Piatti, P, Palvarini, M, De Luca, G, Violini, R, De Leo, A, Filardi, PP, Ferratini, M, Ricca, V, Dai, K, Kamiya, H, Ando, K, Takeda, Y, Morino, Y, Hata, Y, Kimura, K, Kishi, K, Michishita, I, Uehara, H, Higashikata, T, Hirayama, A, Hirooka, K, Sakagami, S, Taguchi, S, Koike, A, Fujinaga, H, Koba, S, Kozuma, K, Kawasaki, T, Ono, Y, Shimizu, M, Katsuda, Y, Wada, A, Shinke, T, Kimura, T, Ako, J, Fujii, K, Takahashi, T, Sakamoto, T, Furukawa, Y, Sugino, H, Mano, T, Utsu, N, Ito, K, Haraguchi, T, Ueda, Y, Nishibe, A, Masutani, M, Fujimoto, K, Yoon, JH, Kim, SH, Park, HS, Chae, IH, Kim, MH, Jeong, MH, Rha, S, Kim, C, Hong, T, Tahk, SJ, Kim, Y, Busmane, A, Pontaga, N, Strelnieks, A, Mintale, I, Sime, I, Petrulioniene, Z, Kavaliauskiene, R, Jurgaitiene, R, Sakalyte, G, Slapikas, R, Norkiene, S, Misonis, N, Kibarskis, A, Kubilius, R, Bojovski, S, Kedev, S, Lozance, N, Kjovkaroski, A, Doncovska, S, Ong, TK, Kasim, S, Maskon, O, Kandasamy, B, Yusoff, K, Liew, HB, Mohamed, WMIW, Castillo, AG, Calvillo, JC, Campos, PF, Fragoso, JCN, Llamas, EAB, Gamba, MAA, Madrigal, JC, Salas, LGG, Rosas, EL, Diaz, BG, Vazquez, ES, Ackar, AN, Esperon, GAL, Sanchez, CRM, De Leon, MG, Otero, RS, Salmon, GF, Rios, JA, Ruiz, JAG, Breedveld, RW, Hoogslag, PAM, Suryapranata, H, Oomen, A, Wiersma, JJ, Van Der Wal, RMA, Van Huysduynen-Monraats, PSH, Karalis, I, Verdel, GJE, Brueren, BR, Troquay, RPT, Viergever, EP, Al-Windy, NYY, Bartels, GL, Cornel, JH, Hermans, WRM, Herrman, JPR, Bos, RJ, Groutars, RGEJ, Van Der Zwaan, CC, Kaplan, R, Ronner, E, Groenemeijer, BE, Bronzwaer, PNA, Liem, AAH, Rensing, BJWM, Bokern, MJJA, Nijmeijer, R, Hersbach, FMRJ, Willems, FF, Gosselink, ATM, Elliott, J, Wilkins, G, Fisher, R, Scott, D, Hart, H, Stewart, R, Harding, S, Ternouth, I, Fisher, N, Aitken, D, Anscombe, R, Davidson, L, Tomala, T, Nygard, O, Sparby, JA, Andersen, K, Gullestad, L, Jortveit, J, Munk, PS, Singsaas, EG, Halvorsen, S, Hurtig, U, Flores, RMC, Ticona, JRC, Velasquez, JRD, Miguel, SAN, Perez, ESS, Chambilla, JMC, Ayala, CAC, Leon, RPC, Gonzales, RJV, Zuniga, JDH, Cosavalente, LAC, Mannucci, JEB, Landeo, JH, Navarro, NCL, Concha, YMR, Chavez, VER, Hernandez, HAA, Nunez, CAZ, Ramos, WM, Ferrolino, A, Sy, RAG, Tirador, L, Sy, RG, Matiga, G, Coching, RM, Bernan, A, Rogelio, G, Morales, DD, Tan, E, Sulit, DJ, Wlodarczak, A, Jaworska, K, Skonieczny, G, Pawlowicz, L, Wojewod, P, Busz-Papiez, B, Bednarski, J, Goch, A, Staneta, P, Dulak, E, Budaj, A, Saminsk, K, Krasowski, W, Sudnik, W, Zurakowski, A, Skorski, M, Lysek, R, Miklaszewicz, B, Kubica, J, Lipko, JA, Kostarska-Srokosz, E, Piepiorka, M, Drzewiecka, A, Sciborski, R, Stasiewski, A, Blicharski, T, Bystryk, L, Szpajer, M, Korol, M, Czerski, T, Mirek-Bryniarska, E, Gniot, J, Lubinski, A, Gorny, J, Franek, E, Raczak, G, Szwed, H, Monteiro, P, Bastos, JM, Pereira, HH, Martins, D, Morais, J, Seixo, F, Mendonca, C, Botelho, A, Minescu, B, Istratoaie, O, Tesloianu, DN, Dorobantu, M, Cristian, G, Podoleanu, CGC, Constantinescu, MCA, Bengus, CM, Militaru, C, Rosu, D, Parepa, IR, Matei, AV, Alexandru, TM, Coman, I, Cioranu, RS, Dimulescu, D, Shvarts, Y, Orlikova, O, Kobalava, Z, Barbarash, OL, Markov, V, Lyamina, N, Gordienko, A, Zrazhevsky, K, Vishnevsky, AY, Gurevich, V, Stryuk, R, Lomakin, NV, Bokarev, I, Shalaev, S, Khaisheva, L, Chizhov, P, Viktorova, I, Osokina, N, Akatova, E, Chumakova, G, Libov, I, Voevoda, MI, Tretyakova, TV, Baranov, E, Shustov, S, Yakushin, S, Gordeev, I, Khasanov, N, Reshetko, O, Sotnikova, T, Molchanova, O, Nikolaev, K, Gapon, L, Baranova, E, Shogenov, Z, Kosmachova, E, Karpov, Y, Povzun, A, Egorova, L, Tyrenko, VV, Ivanov, IG, Kanorsky, S, Simic, D, Ivanovic, N, Davidovic, G, Tasic, N, Asanin, MR, Stojic, S, Apostolovic, SR, Ilic, S, Putnikovic, B, Stankovic, A, Arandjelovic, A, Radovanovic, S, Ristic, AD, Balinovac, J, Dincic, DV, Seferovic, P, Dodic, S, Dimkovic, S, Poh, KK, Ong, HY, Micko, K, Nociar, J, Pella, D, Fulop, P, Hranai, M, Palka, J, Mazur, J, Majercak, I, Dzupina, A, Fazekas, F, Gonsorcik, J, Bugan, V, Selecky, J, Kamensky, G, Strbova, J, Smik, R, Dukat, A, Olexa, P, Zuran, I, Poklukar, J, Suligoj, NC, Cevc, M, Cyster, HP, Ranjith, N, Corbett, C, Bayat, J, Makotoko, EM, Kapp, IE, Basson, MMD, Lottering, H, Van Zyl, LJ, Sebastian, PJ, Pillay, T, Saaiman, JA, Commerford, PJ, Cassimjee, S, Ebrahim, IO, Sarvan, M, Mynhardt, JH, Reuter, H, Moodley, R, Vida, M, Fillat, ARC, Peris, VB, Jimenez, FF, Marin, F, Fernandez, JMC, Gil-Extremera, B, Diz, FW, Garcia-Dorado, D, Iniguez, A, Fernandez, JT, Gonzalez-Juanatey, JR, Portales, JF, Murillo, FC, Pericas, LM, Zamorano, JL, Martin, MD, Cortada, JB, Martin, JJA, Fernandez, JRD, Fernandez, JFD, Lledo, JAG, Sales, JC, Rodriguez, JB, Tragant, GG, Benedicto, A, Gonzalez-Juanatey, C, Potau, MC, Perez, IP, De La Tassa, CM, Rincon, PLO, Recena, JB, Escudier, JM, Payeras, AC, Orcajo, NA, Valdivielso, P, Constantine, G, Haniffa, R, Tissera, N, Amarasekera, S, Fernando, N, Jayawardena, J, Santharaj, W, Ekanayaka, R, Mendis, S, Senaratne, V, Mayurathan, G, Sirisena, T, Rajapaksha, A, Herath, JI, Amarasena, N, Berglund, S, Rasmanis, G, Witt, N, Mourtzinis, G, Nicol, P, Hansen, O, Romeo, S, Jensen, SA, Torstensson, I, Ahremark, U, Sundelin, T, Moccetti, T, Muller, C, Mach, F, Binder, R, Tsai, WC, Ueng, KC, Lai, WT, Liu, ME, Hwang, JJ, Yin, WH, Hsieh, IC, Kuo, JY, Huang, TY, Fang, CY, Kaewsuwanna, P, Soonfuang, W, Jintapakorn, W, Sukonthasarn, A, Wongpraparut, N, Sastravaha, K, Sansanayudh, N, Kehasukcharoen, W, Piyayotai, D, Chotnoparatpat, P, Camsari, A, Kultursay, H, Mutlu, B, Ersanli, M, Demirtas, M, Kirma, C, Ural, E, Koldas, L, Karpenko, O, Prokhorov, A, Vakaluyk, I, Myshanych, H, Reshotko, D, Batushkin, V, Rudenko, L, Kovalskyi, I, Kushnir, M, Tseluyko, V, Mostovoy, Y, Stanislavchuk, M, Kyiak, Y, Karpenko, Y, Malynovsky, Y, Klantsa, A, Kutniy, O, Amosova, E, Tashchuk, V, Leshchuk, O, Rishko, M, Kopytsya, M, Yagensky, A, Vatutin, M, Bagriy, A, Barna, OM, Ushakov, O, Dzyak, G, Goloborodko, B, Rudenko, A, Zheleznyy, V, Trevelyan, J, Zaman, A, Lee, K, Moriarty, A, Aggarwal, RK, Clifford, P, Wong, YK, Iqbal, SM, Subkovas, E, Braganza, D, Sarkar, D, Storey, R, Griffiths, H, Mcclure, S, Muthusamy, R, Kurian, J, Levy, T, Barr, C, Kadr, H, Gerber, R, Simaitis, A, Soran, H, Mathur, A, Brodison, A, Oliver, R, Mudawi, T, Reynolds, T, Sharman, D, Butler, R, Wilkinson, P, Lip, GYH, Halcox, J, Vardi, G, Baldari, D, Brabham, D, Treasure, C, Dahl, C, Palmer, B, Wiseman, A, Puri, S, Mohart, AE, Ince, C, Flores, E, Wright, S, Cheng, SC, Rosenberg, M, Rogers, W, Kosinski, E, Forgosh, L, Waltman, J, Khan, M, Shoukfeh, M, Dagher, G, Lieber, I, Kumar, P, East, C, Krichmar, P, White, L, Knickelbine, T, Haldis, T, Gillespie, E, Suh, D, Arif, I, Akhter, F, Carlson, E, D'Urso, M, El-Ahdab, F, Nelson, W, Harris, B, Cohen, S, Carter, L, Sabatino, K, Haddad, T, Malik, A, Rao, S, Mulkay, A, Jovin, I, Klancke, K, Malhotra, V, Devarapalli, SK, Koren, M, Chandna, H, Dodds, G, Janik, M, Moran, J, Sumner, A, Kobayashi, J, Davis, W, Yazdani, S, Pasquini, J, Thakkar, M, Vedere, A, Leimbach, W, Rider, J, Singh, N, Shah, AV, Janosik, D, Pepine, C, Berman, B, Gelormini, J, Daniels, C, Keating, F, Kondo, NI, Shetty, S, Waider, W, Takata, T, Abu-Fadel, M, Shah, V, Aggarwal, R, Izzo, M, Kumar, A, Hattler, B, Link, C, Bortnick, A, Kinzfogl, G, Ghitis, A, Larry, J, Teufel, E, Kuhlman, P, Mclaurin, B, Zhang, WW, Thew, S, Abbas, J, White, M, Ranadive, N, Gring, C, Henderson, D, Schuchard, T, Farhat, N, Kline, G, Mahal, S, Whitaker, J, Speirs, S, Andersen, R, Daboul, N, Horwitz, P, Ponce, G, Jafar, Z, Mcgarvey, J, Panchal, V, Voyce, S, Blok, T, Sheldon, W, Azizad, MM, Schmalfuss, C, Picone, M, Herzog, W, Lindsey, J, Nowins, R, Lepor, N, El Shahawy, M, Weintraub, H, Irimpen, A, May, W, Galski, T, Chu, A, Mody, F, Hodes, Z, Rose, G, Fairlamb, J, Lambert, C, Raisinghani, A, Abbate, A, King, M, Carey, C, Gerber, J, Younis, L, Park, H, Vidovich, M, Knutson, T, Friedman, D, Chaleff, F, Loussararian, A, Rozeman, P, Kimmelstiel, C, Silver, K, Foster, M, Tonnessen, G, Amlani, M, Wali, A, Malozzi, C, Wattanakit, K, O'Donnell, PJ, Singal, D, Jaffrani, N, Banuru, S, Fisher, D, Xenakis, M, Perlmutter, N, Bhagwat, R, Strader, J, Akyea-Djamson, A, Labroo, A, Marais, HJ, Claxton, E, Berk, M, Rossi, P, Joshi, P, Khaira, AS, Kumkumian, G, Lupovitch, S, Purow, J, Welka, S, Hoffman, D, Fischer, S, Soroka, E, Eagerton, D, Pancholy, S, Ray, M, Farrar, M, Pollock, S, French, WJ, Diamantis, S, Gimple, L, Neustel, M, Schwartz, S, Pereira, E, Spriggs, D, Strain, J, Vo, A, Chane, M, Hall, J, Vijay, N, Lotun, K, Lester, FM, Nahhas, A, Pope, T, Nager, P, Vohra, R, Bashir, R, Ahmed, H, Berlowitz, M, Fishberg, R, Barrucco, R, Yang, E, Radin, M, Sporn, D, Eisenberg, S, Landzberg, J, Mcgough, M, Turk, S, Schwartz, M, Sundram, PS, Jain, D, Zainea, M, Bayron, C, Karlsberg, R, Lui, H, Keen, W, Westerhausen, D, Khurana, S, Agarwal, H, Birchem, J, Penny, W, Chang, M, Murphy, S, Schifferdecker, B, Gilbert, JM, Chalavarya, G, Eaton, C, Schmedtje, JF, Christenson, S, Denham, D, Macdonell, A, Gibson, P, Rahman, A, Al Joundi, T, Conrad, G, Kotha, P, Love, M, Giesler, G, Rubenstein, H, Akright, L, Krawczyk, J, Wells, T, Welker, J, Foster, R, Gilmore, R, Anderson, J, Jacoby, D, Gardner, G, Dandillaya, R, Vora, K, Kostis, J, Hunter, J, Laxson, D, Ball, E, Camp, A, Lopes, R, Egydio, F, Kawakami, A, Oliveira, J, Wozniak, J, Matthews, A, Ratky, C, Valiris, J, Berdan, L, Hepditch, A, Quintero, K, Rorick, T, Westbrook, M, Pascual, A, Rovito, C, Bezault, M, Drouet, E, Simon, T, Alsweiler, C, Luyten, A, Aylward, P, Butters, J, Griffith, L, Shaw, M, Hagstrom, E, Grunberg, L, Islam, S, Bregeault, MF, Bougon, N, Faustino, D, Fontecave, S, Murphy, J, Tamby, JF, Verrier, M, Agnetti, V, Andersen, D, Badreddine, E, Bekkouche, M, Bouancheau, C, Brigui, I, Brocklehurst, M, Cianciarulo, J, Devaul, D, Domokos, S, Gache, C, Gobillot, C, Guillou, S, Healy, J, Heath, M, Jaiwal, G, Javierre, C, Labeirie, J, Monier, M, Morales, U, Mrabti, A, Mthombeni, B, Okan, B, Smith, L, Sheller, J, Sopena, S, Pellan, V, Benbernou, F, Bengrait, N, Lamoureux, M, Kralova, K, Scemama, M, Bejuit, R, Coulange, A, Berthou, C, Repincay, J, Lorenzato, C, Etienne, A, Gouet, V, Loizeau, V, Normand, M, Ourliac, A, Rondel, C, Adamo, A, Beltran, P, Barraud, P, Dubois-Gache, H, Halle, B, Metwally, L, Mourgues, M, Sotty, M, Vincendet, M, Cotruta, R, Zhu, CY, Fournie-Lloret, D, Morrello, C, Perthuis, A, Picault, P, Zobouyan, I, ODYSSEY OUTCOMES Comm Inve, Ege Üniversitesi, Cardiology, and Internal Medicine
Subjects: medicine.medical_specialty, Acute coronary syndrome, Time Factors, acute coronary syndrome, alirocumab, global burden of disease, hospitalization, myocardial infarction, PCSK9, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Placebo, Patient Readmission, Risk Assessment, 03 medical and health sciences, Patient Admission, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Angina, Unstable, Hospital Mortality, 030212 general & internal medicine, Myocardial infarction, 03.02. Klinikai orvostan, Dyslipidemias, Alirocumab, Out of hospital, business.industry, Anticholesteremic Agents, Cholesterol, HDL, Cholesterol hdl, Cholesterol, LDL, medicine.disease, Treatment Outcome, Drug Therapy, Combination, Human medicine, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business, Cardiovascular outcomes, Biomarkers
Abstract: Sherwood, Matthew/0000-0002-4305-5883; Abbate, Antonio/0000-0002-1930-785X; Moris, Cesar/0000-0002-2871-190X; Ersanli, Murat/0000-0003-1847-3087; Taskinen, Marja-Riitta/0000-0002-6229-3588; bastos, jose/0000-0002-9526-3123; Reshetko, Olga/0000-0003-3107-7636; Nikolaev, Konstantin/0000-0003-4601-6203; Leonardi, Sergio/0000-0002-4800-6132; Raffel, Owen C/0000-0001-5470-7050; Racca, Vittorio/0000-0002-4465-3789; Podoleanu, Cristian/0000-0001-9987-2519; Gislason, Gunnar H/0000-0002-0548-402X; Muenzel, Thomas/0000-0001-5503-4150; Tse, Hung Fat/0000-0002-9578-7808; Chumakova, Galina A/0000-0002-2810-6531, WOS: 000502609000004, PubMed: 31707826, Background: in ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab was compared with placebo, added to high-intensity or maximum tolerated statin treatment after acute coronary syndrome in 18924 patients. Alirocumab reduced first occurrence of the primary composite end point-coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or hospitalization for unstable angina-as well as total nonfatal cardiovascular events and all-cause deaths. the present analysis determined whether alirocumab reduced total (first and subsequent) hospitalizations and death and increased days alive and out of hospital (DAOH) and percent DAOH in ODYSSEY OUTCOMES. Methods and Results: in prespecified analyses, hazard functions for total hospitalizations and death were jointly estimated by a semiparametric model, while in post hoc analyses, DAOH and percent DAOH were compared between treatment groups with Poisson regression and one-inflated beta regression, respectively. With 16629 total hospitalizations and 726 deaths, 331 fewer hospitalizations, and 58 fewer deaths were observed with alirocumab compared with placebo, translating to 15.6 total hospitalizations or deaths avoided with alirocumab per 1000 patient-years of assigned treatment. Alirocumab reduced total hospitalizations (hazard ratio, 0.96 [95% CI, 0.92-1.00]; P=0.04) and increased DAOH relative to placebo (rate ratio, 1.003 [95% CI, 1.000-1.007]; P=0.05), primarily through a reduction in days dead (rate ratio, 0.847 [95% CI, 0.728-0.986]; P=0.03). Patients randomized to alirocumab were also more likely to survive to the end of the study without hospitalization (odds ratio, 1.06 [95% CI, 1.00-1.13]; P=0.03). Conclusions: Alirocumab reduced total hospitalizations with corresponding small increases in DAOH and percent DAOH. These outcomes provide alternative patient-centered metrics to capture the totality of alirocumab clinical efficacy after acute coronary syndrome. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01663402., Fondation Assistance Publique-Hopitaux de Paris, Paris, France, We thank the patients, study coordinators, and investigators who participated in this trial. Sophie Rushton-Smith, PhD (MedLink Healthcare Communications, London) provided editorial assistance in the preparation of the article (limited to editing for style, referencing, and figure and table editing) and was funded by Fondation Assistance Publique-Hopitaux de Paris, Paris, France.
Published: 2019

38. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Franceschini, N, Giambartolomei, C, de Vries, PS, Finan, C, Bis, JC, Huntley, RP, Lovering, RC, Tajuddin, SM, Winkler, TW, Graff, M, Kavousi, M, Dale, C, Smith, AV, Hofer, E, van Leeuwen, EM, Nolte, IM, Lu, L, Scholz, M, Sargurupremraj, M, Pitkänen, N, Franzén, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, SJ, Musani, SK, Schminke, U, Palmas, W, Isaacs, A, Correa, A, Zonderman, AB, Hofman, A, Teumer, A, Cox, AJ, Uitterlinden, AG, Wong, A, Smit, AJ, Newman, AB, Britton, A, Ruusalepp, A, Sennblad, B, Hedblad, B, Pasaniuc, B, Penninx, BW, Langefeld, CD, Wassel, CL, Tzourio, C, Fava, C, Baldassarre, D, O’Leary, DH, Teupser, D, Kuh, D, Tremoli, E, Mannarino, E, Grossi, E, Boerwinkle, E, Schadt, EE, Ingelsson, E, Veglia, F, Rivadeneira, F, Beutner, F, Chauhan, G, Heiss, G, Snieder, H, Campbell, H, Völzke, H, Markus, HS, Deary, IJ, Jukema, JW, de Graaf, J, Price, J, Pott, J, Hopewell, JC, Liang, J, Thiery, J, Engmann, J, Gertow, K, Rice, K, Taylor, KD, Dhana, K, Kiemeney, LALM, Lind, L, Raffield, LM, Launer, LJ, Holdt, LM, Dörr, M, Dichgans, M, Traylor, M, Sitzer, M, Kumari, M, Kivimaki, M, Nalls, MA, Melander, O, Raitakari, O, Franco, OH, Rueda-Ochoa, OL, Roussos, P, Whincup, PH, Amouyel, P, and Giral, P
Subjects: Aging, MEGASTROKE Consortium, Quantitative Trait Loci, ADAMTS9 Protein, Coronary Disease, Cardiovascular, Polymorphism, Single Nucleotide, Carotid Intima-Media Thickness, Protein-Lysine 6-Oxidase, Risk Factors, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Aetiology, Polymorphism, Heart Disease - Coronary Heart Disease, Plaque, Atherosclerotic, Human Genome, Single Nucleotide, Atherosclerosis, Plaque, Atherosclerotic, Brain Disorders, Stroke, Heart Disease, cardiovascular system, Amino Acid Oxidoreductases, Lod Score, Genome-Wide Association Study
Abstract: © 2018, The Author(s). Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Published: 2018

39. Profile of and risk factors for poststroke cognitive impairment in diverse ethnoregional groups

Author: Lo, JW, Crawford, JD, Desmond, DW, Godefroy, O, Jokinen, H, Mahinrad, S, Bae, HJ, Lim, JS, Köhler, S, Douven, E, Staals, J, Chen, C, Xu, X, Chong, EJ, Akinyemi, RO, Kalaria, RN, Ogunniyi, A, Barbay, M, Roussel, M, Lee, BC, Srikanth, VK, Moran, C, Kandiah, N, Chander, RJ, Sabayan, B, Jukema, JW, Melkas, S, Erkinjuntti, T, Brodaty, H, Bordet, R, Bombois, S, Hénon, H, Lipnicki, DM, Kochan, NA, Sachdev, PS, Lo, JW, Crawford, JD, Desmond, DW, Godefroy, O, Jokinen, H, Mahinrad, S, Bae, HJ, Lim, JS, Köhler, S, Douven, E, Staals, J, Chen, C, Xu, X, Chong, EJ, Akinyemi, RO, Kalaria, RN, Ogunniyi, A, Barbay, M, Roussel, M, Lee, BC, Srikanth, VK, Moran, C, Kandiah, N, Chander, RJ, Sabayan, B, Jukema, JW, Melkas, S, Erkinjuntti, T, Brodaty, H, Bordet, R, Bombois, S, Hénon, H, Lipnicki, DM, Kochan, NA, and Sachdev, PS
Abstract: ObjectiveTo address the variability in prevalence estimates and inconsistencies in potential risk factors for poststroke cognitive impairment (PSCI) using a standardized approach and individual participant data (IPD) from international cohorts in the Stroke and Cognition Consortium (STROKOG) consortium.MethodsWe harmonized data from 13 studies based in 8 countries. Neuropsychological test scores 2 to 6 months after stroke or TIA and appropriate normative data were used to calculate standardized cognitive domain scores. Domain-specific impairment was based on percentile cutoffs from normative groups, and associations between domain scores and risk factors were examined with 1-stage IPD meta-analysis.ResultsIn a combined sample of 3,146 participants admitted to hospital for stroke (97%) or TIA (3%), 44% were impaired in global cognition and 30% to 35% were impaired in individual domains 2 to 6 months after the index event. Diabetes mellitus and a history of stroke were strongly associated with poorer cognitive function after covariate adjustments; hypertension, smoking, and atrial fibrillation had weaker domain-specific associations. While there were no significant differences in domain impairment among ethnoracial groups, some interethnic differences were found in the effects of risk factors on cognition.ConclusionsThis study confirms the high prevalence of PSCI in diverse populations, highlights common risk factors, in particular diabetes mellitus, and points to ethnoracial differences that warrant attention in the development of prevention strategies.
Published: 2019

40. World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions

Author: Kaptoge, S, Pennells, L, De Bacquer, D, Cooney, MT, Kavousi, M, Stevens, G, Riley, LM, Savin, S, Khan, T, Altay, S, Amouyel, P, Assmann, G, Bell, S, Ben-Shlomo, Y, Berkman, L, Beulens, JW, Björkelund, C, Blaha, M, Blazer, DG, Bolton, T, Bonita Beaglehole, R, Brenner, H, Brunner, EJ, Casiglia, E, Chamnan, P, Choi, YH, Chowdry, R, Coady, S, Crespo, CJ, Cushman, M, Dagenais, GR, D'Agostino, RB, Daimon, M, Davidson, KW, Engström, G, Ford, I, Gallacher, J, Gansevoort, RT, Gaziano, TA, Giampaoli, S, Grandits, G, Grimsgaard, S, Grobbee, DE, Gudnason, V, Guo, Q, Tolonen, H, Humphries, S, Iso, H, Jukema, JW, Kauhanen, J, Kengne, AP, Khalili, D, Koenig, W, Kromhout, D, Krumholz, H, Lam, TH, Laughlin, G, Marín Ibañez, A, Meade, TW, Moons, KGM, Nietert, PJ, Ninomiya, T, Nordestgaard, BG, O'Donnell, C, Palmieri, L, Patel, A, Perel, P, Price, JF, Providencia, R, Ridker, PM, Rodriguez, B, Rosengren, A, Roussel, R, Sakurai, M, Salomaa, V, Sato, S, Schöttker, B, Shara, N, Shaw, JE, Shin, HC, Simons, LA, Sofianopoulou, E, Sundström, J, Völzke, H, Wallace, RB, Wareham, NJ, Willeit, P, Wood, D, Wood, A, Zhao, D, Woodward, M, Danaei, G, Roth, G, Mendis, S, Onuma, O, Varghese, C, Ezzati, M, Graham, I, Jackson, R, Danesh, J, Kaptoge, S, Pennells, L, De Bacquer, D, Cooney, MT, Kavousi, M, Stevens, G, Riley, LM, Savin, S, Khan, T, Altay, S, Amouyel, P, Assmann, G, Bell, S, Ben-Shlomo, Y, Berkman, L, Beulens, JW, Björkelund, C, Blaha, M, Blazer, DG, Bolton, T, Bonita Beaglehole, R, Brenner, H, Brunner, EJ, Casiglia, E, Chamnan, P, Choi, YH, Chowdry, R, Coady, S, Crespo, CJ, Cushman, M, Dagenais, GR, D'Agostino, RB, Daimon, M, Davidson, KW, Engström, G, Ford, I, Gallacher, J, Gansevoort, RT, Gaziano, TA, Giampaoli, S, Grandits, G, Grimsgaard, S, Grobbee, DE, Gudnason, V, Guo, Q, Tolonen, H, Humphries, S, Iso, H, Jukema, JW, Kauhanen, J, Kengne, AP, Khalili, D, Koenig, W, Kromhout, D, Krumholz, H, Lam, TH, Laughlin, G, Marín Ibañez, A, Meade, TW, Moons, KGM, Nietert, PJ, Ninomiya, T, Nordestgaard, BG, O'Donnell, C, Palmieri, L, Patel, A, Perel, P, Price, JF, Providencia, R, Ridker, PM, Rodriguez, B, Rosengren, A, Roussel, R, Sakurai, M, Salomaa, V, Sato, S, Schöttker, B, Shara, N, Shaw, JE, Shin, HC, Simons, LA, Sofianopoulou, E, Sundström, J, Völzke, H, Wallace, RB, Wareham, NJ, Willeit, P, Wood, D, Wood, A, Zhao, D, Woodward, M, Danaei, G, Roth, G, Mendis, S, Onuma, O, Varghese, C, Ezzati, M, Graham, I, Jackson, R, and Danesh, J
Abstract: Background: To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. Methods: In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40–80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. Findings: Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629–0·741) to 0·833 (0·783–0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a
Published: 2019

41. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author: Chauhan, G, Adams, HHH, Satizabal, CL, Bis, JC, Teumer, A, Sargurupremraj, M, Hofer, E, Trompet, S, Hilal, S, Smith, AV, Jian, X, Malik, R, Traylor, M, Pulit, SL, Amouyel, P, Mazoyer, B, Zhu, YC, Kaffashian, S, Schilling, S, Beecham, GW, Montine, TJ, Schellenberg, GD, Kjartansson, O, Guðnason, V, Knopman, DS, Griswold, ME, Windham, BG, Gottesman, RF, Mosley, TH, Schmidt, R, Saba, Y, Schmidt, H, Takeuchi, F, Yamaguchi, S, Nabika, T, Kato, N, Rajan, KB, Aggarwal, NT, De Jager, PL, Evans, DA, Psaty, BM, Rotter, JI, Rice, K, Lopez, OL, Liao, J, Chen, C, Cheng, CY, Wong, TY, Ikram, MK, van der Lee, SJ, Amin, N, Chouraki, V, Destefano, AL, Aparicio, HJ, Romero, JR, Maillard, P, Decarli, C, Wardlaw, JM, Del C. Valdés Hernández, M, Luciano, M, Liewald, D, Deary, IJ, Starr, JM, Bastin, ME, Maniega, SM, Slagboom, PE, Beekman, M, Deelen, J, Uh, HW, Lemmens, R, Brodaty, H, Wright, MJ, Ames, D, Boncoraglio, GB, Hopewell, JC, Beecham, AH, Blanton, SH, Wright, CB, Sacco, RL, Wen, W, Thalamuthu, A, Armstrong, NJ, Chong, E, Schofield, PR, Kwok, JB, van der Grond, J, Stott, DJ, Ford, I, Jukema, JW, Vernooij, MW, Hofman, A, Uitterlinden, AG, van der Lugt, A, Wittfeld, K, Grabe, HJ, Hosten, N, von Sarnowski, B, Völker, U, Levi, C, Jimenez-Conde, J, Chauhan, G, Adams, HHH, Satizabal, CL, Bis, JC, Teumer, A, Sargurupremraj, M, Hofer, E, Trompet, S, Hilal, S, Smith, AV, Jian, X, Malik, R, Traylor, M, Pulit, SL, Amouyel, P, Mazoyer, B, Zhu, YC, Kaffashian, S, Schilling, S, Beecham, GW, Montine, TJ, Schellenberg, GD, Kjartansson, O, Guðnason, V, Knopman, DS, Griswold, ME, Windham, BG, Gottesman, RF, Mosley, TH, Schmidt, R, Saba, Y, Schmidt, H, Takeuchi, F, Yamaguchi, S, Nabika, T, Kato, N, Rajan, KB, Aggarwal, NT, De Jager, PL, Evans, DA, Psaty, BM, Rotter, JI, Rice, K, Lopez, OL, Liao, J, Chen, C, Cheng, CY, Wong, TY, Ikram, MK, van der Lee, SJ, Amin, N, Chouraki, V, Destefano, AL, Aparicio, HJ, Romero, JR, Maillard, P, Decarli, C, Wardlaw, JM, Del C. Valdés Hernández, M, Luciano, M, Liewald, D, Deary, IJ, Starr, JM, Bastin, ME, Maniega, SM, Slagboom, PE, Beekman, M, Deelen, J, Uh, HW, Lemmens, R, Brodaty, H, Wright, MJ, Ames, D, Boncoraglio, GB, Hopewell, JC, Beecham, AH, Blanton, SH, Wright, CB, Sacco, RL, Wen, W, Thalamuthu, A, Armstrong, NJ, Chong, E, Schofield, PR, Kwok, JB, van der Grond, J, Stott, DJ, Ford, I, Jukema, JW, Vernooij, MW, Hofman, A, Uitterlinden, AG, van der Lugt, A, Wittfeld, K, Grabe, HJ, Hosten, N, von Sarnowski, B, Völker, U, Levi, C, and Jimenez-Conde, J
Abstract: Objective To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p[BI]= 4.4 × 10-10; p [SSBI] = 1.2 × 10 -4), diabetes (p[BI] = 1.7 × 10 -8; p [SSBI] = 2.8 × 10 -3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significan
Published: 2019

42. Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes

Author: Roe, MT, Li, QH, Bhatt, DL, Bittner, VA, Diaz, R, Goodman, SG, Harrington, RA, Jukema, JW, Lopez-Jaramillo, P, Lopes, RD, Louie, MJ, Moriarty, PM, Szarek, M, Vogel, R, White, HD, Zeiher, AM, Simoons, Maarten, Sijbrands, E.J.G., Baccara-Dinet, M, Steg, G, Schwartz, GG, Roe, MT, Li, QH, Bhatt, DL, Bittner, VA, Diaz, R, Goodman, SG, Harrington, RA, Jukema, JW, Lopez-Jaramillo, P, Lopes, RD, Louie, MJ, Moriarty, PM, Szarek, M, Vogel, R, White, HD, Zeiher, AM, Simoons, Maarten, Sijbrands, E.J.G., Baccara-Dinet, M, Steg, G, and Schwartz, GG
Published: 2019

43. Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Author: White, HD, Steg, PG, Szarek, M, Bhatt, DL, Bittner, VA, Diaz, R, Edelberg, JM, Erglis, A, Goodman, SG, Hanotin, C, Harrington, RA, Jukema, JW, Lopes, RD, Mahaffey, KW, Moryusef, A, Pordy, R, Roe, MT, Sritara, P, Tricoci, P, Simoons, Maarten, Sijbrands, E.J.G., Zeiher, AM, Schwartz, GG, White, HD, Steg, PG, Szarek, M, Bhatt, DL, Bittner, VA, Diaz, R, Edelberg, JM, Erglis, A, Goodman, SG, Hanotin, C, Harrington, RA, Jukema, JW, Lopes, RD, Mahaffey, KW, Moryusef, A, Pordy, R, Roe, MT, Sritara, P, Tricoci, P, Simoons, Maarten, Sijbrands, E.J.G., Zeiher, AM, and Schwartz, GG
Published: 2019

44. Subclinical thyroid dysfunction and depressive symptoms: protocol for a systematic review and individual participant data meta-analysis of prospective cohort studies

Author: Wildisen, L, Moutzouri, E, Beglinger, S, Syrogiannouli, L, Cappola, AR, Asvold, BO, Bakker, SJ, Ceresini, G, Dullaart, R, Ferrucci, L, Grabe, H, Jukema, JW, Nauck, M, Trompet, S, Volzke, H, Westendorp, RG, Gussekloo, J, Peeters, Robin, Kloppel, S, Aujesky, D, Bauer, DC, Rodondi, N, Del Giovane, C, Feller, M, Wildisen, L, Moutzouri, E, Beglinger, S, Syrogiannouli, L, Cappola, AR, Asvold, BO, Bakker, SJ, Ceresini, G, Dullaart, R, Ferrucci, L, Grabe, H, Jukema, JW, Nauck, M, Trompet, S, Volzke, H, Westendorp, RG, Gussekloo, J, Peeters, Robin, Kloppel, S, Aujesky, D, Bauer, DC, Rodondi, N, Del Giovane, C, and Feller, M
Published: 2019

45. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals

Author: Deelen, J, Kettunen, J, Fischer, K, van der Spek, Ashley, Trompet, S, Kastenmuller, G, Boyd, A, Zierer, J, van den Akker, EB, Ala-Korpela, M, Amin, Najaf, Demirkan, Ayse, Ghanbari, Mohsen, van Heemst, D, Ikram, Arfan, van Klinken, JB, Mooijaart, SP, Peters, A, Salomaa, V, Sattar, N, Spector, TD, Tiemeier, Henning, Verhoeven, Adrie, Waldenberger, M, Wurtz, P, Smith, GD, Metspalu, A, Perola, M, Menni, C, Geleijnse, JM, Drenos, F, Beekman, M, Jukema, JW, Duijn, CM, Slagboom, PE (Eline), Deelen, J, Kettunen, J, Fischer, K, van der Spek, Ashley, Trompet, S, Kastenmuller, G, Boyd, A, Zierer, J, van den Akker, EB, Ala-Korpela, M, Amin, Najaf, Demirkan, Ayse, Ghanbari, Mohsen, van Heemst, D, Ikram, Arfan, van Klinken, JB, Mooijaart, SP, Peters, A, Salomaa, V, Sattar, N, Spector, TD, Tiemeier, Henning, Verhoeven, Adrie, Waldenberger, M, Wurtz, P, Smith, GD, Metspalu, A, Perola, M, Menni, C, Geleijnse, JM, Drenos, F, Beekman, M, Jukema, JW, Duijn, CM, and Slagboom, PE (Eline)
Published: 2019

46. Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study

Author: Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaëlsson, K, Markus, HS, Malik, R, Chauhan, G, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, RM, Benavente, OR, Bevan, S, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaëlsson, K, Markus, HS, Malik, R, Chauhan, G, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, RM, Benavente, OR, Bevan, S, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, and Rothwell, PM
Abstract: © 2019 American Academy of Neurology. ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2019

47. ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels

Author: Zwarts, KY, Clee, SM, Zwinderman, AH, Engert, JC, Singaraja, R, Loubser, O, James, E, Roomp, K, Hudson, TJ, Jukema, JW, Kastelein, JJP, and Hayden, MR
Published: 2002

48. Defining the role of common variation in the genomic and biological architecture of adult human height

Author: Wood, Ar, Esko, T, Yang, J, Vedantam, S, Pers, Th, Gustafsson, S, Chu, Ay, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, Ml, Croteau Chonka DC, Day, Fr, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, Au, Karjalainen, J, Lo, Ks, Locke, Ae, Mägi, R, Mihailov, E, Porcu, E, Randall, Jc, Scherag, A, Vinkhuyzen, Aa, Westra, Hj, Winkler, Tw, Workalemahu, T, Zhao, Jh, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, Gb, Feenstra, B, Feitosa, Mf, Fischer, K, Fraser, Rm, Goel, A, Gong, J, Justice, Ae, Kanoni, S, Kleber, Me, Kristiansson, K, Lim, U, Lotay, V, Lui, Jc, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, Ma, Nyholt, Dr, Palmer, Cd, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, Js, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, Rj, Sung, Yj, Tanaka, T, Teumer, A, Trompet, S, van der Laan SW, van Setten, J, Van Vliet Ostaptchouk JV, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Arnlöv, J, Arscott, Gm, Bandinelli, S, Barrett, A, Bellis, C, Bennett, Aj, Berne, C, Blüher, M, Bolton, Jl, Böttcher, Y, Boyd, Ha, Bruinenberg, M, Buckley, Bm, Buyske, S, Caspersen, Ih, Chines, Ps, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, Ew, De Jong PA, Deelen, J, Delgado, G, Denny, Jc, Dhonukshe Rutten, R, Dimitriou, M, Doney, As, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, Me, Geller, F, Giedraitis, V, Go, As, Grallert, H, Grammer, Tb, Gräßler, J, Grönberg, H, de Groot LC, Groves, Cj, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hannemann, A, Hartman, Ca, Hassinen, M, Hayward, C, Heard Costa NL, Helmer, Q, Hemani, G, Henders, Ak, Hillege, Hl, Hlatky, Ma, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat JJ, Illig, T, Isaacs, A, James, Al, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, An, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, Pk, Mahajan, A, Maillard, M, Mcardle, Wl, Mckenzie, Ca, Mclachlan, S, Mclaren, Pj, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, Kl, Morken, Ma, Müller, G, Müller Nurasyid, M, Musk, Aw, Narisu, N, Nauck, M, Nolte, Im, Nöthen, Mm, Oozageer, L, Pilz, S, Rayner, Nw, Renstrom, F, Robertson, Nr, Rose, Lm, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, Fr, Schunkert, H, Scott, Ra, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, Jh, Smith, Av, Smolonska, J, Stanton, Av, Stirrups, K, Stott, Dj, Stringham, Hm, Sundström, J, Swertz, Ma, Syvänen, Ac, Tayo, Bo, Thorleifsson, G, Tyrer, Jp, van Dijk, S, van Schoor NM, van der Velde, N, van Heemst, D, van Oort FV, Vermeulen, Sh, Verweij, N, Vonk, Jm, Waite, Ll, Waldenberger, M, Wennauer, R, Wilkens, Lr, Willenborg, C, Wilsgaard, T, Wojczynski, Mk, Wong, A, Wright, Af, Zhang, Q, Arveiler, D, Bakker, Sj, Beilby, J, Bergman, Rn, Bergmann, S, Biffar, R, Blangero, J, Boomsma, Di, Bornstein, Sr, Bovet, P, Brambilla, P, Brown, Mj, Campbell, H, Caulfield, Mj, Chakravarti, A, Collins, R, Collins, Fs, Crawford, Dc, Cupples, La, Danesh, J, de Faire, U, den Ruijter HM, Erbel, R, Erdmann, J, Eriksson, Jg, Farrall, M, Ferrannini, Eleuterio, Ferrières, J, Ford, I, Forouhi, Ng, Forrester, T, Gansevoort, Rt, Gejman, Pv, Gieger, C, Golay, A, Gottesman, O, Gudnason, V, Gyllensten, U, Haas, Dw, Hall, As, Harris, Tb, Hattersley, At, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hindorff, La, Hingorani, Ad, Hofman, A, Hovingh, Gk, Humphries, Se, Hunt, Sc, Hypponen, E, Jacobs, Kb, Jarvelin, Mr, Jousilahti, P, Jula, Am, Kaprio, J, Kastelein, Jj, Kayser, M, Kee, F, Keinanen Kiukaanniemi SM, Kiemeney, La, Kooner, Js, Kooperberg, C, Koskinen, S, Kovacs, P, Kraja, At, Kumari, M, Kuusisto, J, Lakka, Ta, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lupoli, S, Madden, Pa, Männistö, S, Manunta, P, Marette, A, Matise, Tc, Mcknight, B, Meitinger, T, Moll, Fl, Montgomery, Gw, Morris, Ad, Morris, Ap, Murray, Jc, Nelis, M, Ohlsson, C, Oldehinkel, Aj, Ong, Kk, Ouwehand, Wh, Pasterkamp, G, Peters, A, 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Hirschhorn, Jn, Frayling, Tm, Epidemiology, Surgery, Public Health, Internal Medicine, Erasmus MC other, Genetic Identification, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Biological Psychology, AIMMS, Functional Genomics, EMGO+ - Lifestyle, Overweight and Diabetes, Wood, AR, Vadantam, S, Hypponen, Elina, Frayling, TM, Wood A.R., Esko T., Yang J., Vedantam S., Pers T.H., Gustafsson S., Chu A.Y., Estrada K., Luan J., Kutalik Z., Amin N., Buchkovich M.L., Croteau-Chonka D.C., Day F.R., Duan Y., Fall T., Fehrmann R., Ferreira T., Jackson A.U., Karjalainen J., Lo K.S., Locke A.E., Magi R., Mihailov E., Porcu E., Randall J.C., Scherag A., Vinkhuyzen A.A.E., Westra H.-J., Winkler T.W., Workalemahu T., Zhao J.H., Absher D., Albrecht E., Anderson D., Baron J., Beekman M., Demirkan A., Ehret G.B., Feenstra B., Feitosa M.F., Fischer K., Fraser R.M., Goel A., Gong J., Justice A.E., Kanoni S., Kleber M.E., Kristiansson K., Lim U., Lotay V., Lui J.C., Mangino M., Leach I.M., Medina-Gomez C., Nalls M.A., Nyholt D.R., Palmer C.D., Pasko D., Pechlivanis S., Prokopenko I., Ried J.S., Ripke S., Shungin D., Stancakova A., Strawbridge R.J., Sung Y.J., Tanaka T., Teumer A., Trompet S., Van Der Laan S.W., Van Setten J., Van Vliet-Ostaptchouk J.V., Wang Z., Yengo L., Zhang W., Afzal U., Arnlov J., Arscott G.M., Bandinelli S., Barrett A., Bellis C., Bennett A.J., Berne C., Bluher M., Bolton J.L., Bottcher Y., Boyd H.A., Bruinenberg M., Buckley B.M., Buyske S., Caspersen I.H., Chines P.S., Clarke R., Claudi-Boehm S., Cooper M., Daw E.W., De Jong P.A., Deelen J., Delgado G., Denny J.C., Dhonukshe-Rutten R., Dimitriou M., Doney A.S.F., Dorr M., Eklund N., Eury E., Folkersen L., Garcia M.E., Geller F., Giedraitis V., Go A.S., Grallert H., Grammer T.B., Grassler J., Gronberg H., De Groot L.C.P.G.M., Groves C.J., Haessler J., Hall P., Haller T., Hallmans G., Hannemann A., Hartman C.A., Hassinen M., Hayward C., Heard-Costa N.L., Helmer Q., Hemani G., Henders A.K., Hillege H.L., Hlatky M.A., Hoffmann W., Hoffmann P., Holmen O., Houwing-Duistermaat J.J., Illig T., Isaacs A., James A.L., Jeff J., Johansen B., Johansson A., Jolley J., Juliusdottir T., Junttila J., Kho A.N., Kinnunen L., Klopp N., Kocher T., Kratzer W., Lichtner P., Lind L., Lindstrom J., Lobbens S., Lorentzon M., Lu Y., Lyssenko V., Magnusson P.K.E., Mahajan A., Maillard M., McArdle W.L., McKenzie C.A., McLachlan S., McLaren P.J., Menni C., Merger S., Milani L., Moayyeri A., Monda K.L., Morken M.A., Muller G., Muller-Nurasyid M., Musk A.W., Narisu N., Nauck M., Nolte I.M., Nothen M.M., Oozageer L., Pilz S., Rayner N.W., Renstrom F., Robertson N.R., Rose L.M., Roussel R., Sanna S., Scharnagl H., Scholtens S., Schumacher F.R., Schunkert H., Scott R.A., Sehmi J., Seufferlein T., Shi J., Silventoinen K., Smit J.H., Smith A.V., Smolonska J., Stanton A.V., Stirrups K., Stott D.J., Stringham H.M., Sundstrom J., Swertz M.A., Syvanen A.-C., Tayo B.O., Thorleifsson G., Tyrer J.P., Van Dijk S., Van Schoor N.M., Van Der Velde N., Van Heemst D., Van Oort F.V.A., Vermeulen S.H., Verweij N., Vonk J.M., Waite L.L., Waldenberger M., Wennauer R., Wilkens L.R., Willenborg C., Wilsgaard T., Wojczynski M.K., Wong A., Wright A.F., Zhang Q., Arveiler D., Bakker S.J.L., Beilby J., Bergman R.N., Bergmann S., Biffar R., Blangero J., Boomsma D.I., Bornstein S.R., Bovet P., Brambilla P., Brown M.J., Campbell H., Caulfield M.J., Chakravarti A., Collins R., Collins F.S., Crawford D.C., Cupples L.A., Danesh J., De Faire U., Den Ruijter H.M., Erbel R., Erdmann J., Eriksson J.G., Farrall M., Ferrannini E., Ferrieres J., Ford I., Forouhi N.G., Forrester T., Gansevoort R.T., Gejman P.V., Gieger C., Golay A., Gottesman O., Gudnason V., Gyllensten U., Haas D.W., Hall A.S., Harris T.B., Hattersley A.T., Heath A.C., Hengstenberg C., Hicks A.A., Hindorff L.A., Hingorani A.D., Hofman A., Hovingh G.K., Humphries S.E., Hunt S.C., Hypponen E., Jacobs K.B., Jarvelin M.-R., Jousilahti P., Jula A.M., Kaprio J., Kastelein J.J.P., Kayser M., Kee F., Keinanen-Kiukaanniemi S.M., Kiemeney L.A., Kooner J.S., Kooperberg C., Koskinen S., Kovacs P., Kraja A.T., Kumari M., Kuusisto J., Lakka T.A., Langenberg C., Le Marchand L., Lehtimaki T., Lupoli S., Madden P.A.F., Mannisto S., Manunta P., Marette A., Matise T.C., McKnight B., Meitinger T., Moll F.L., Montgomery G.W., Morris A.D., Morris A.P., Murray J.C., Nelis M., Ohlsson C., Oldehinkel A.J., Ong K.K., Ouwehand W.H., Pasterkamp G., Peters A., Pramstaller P.P., Price J.F., Qi L., Raitakari O.T., Rankinen T., Rao D.C., Rice T.K., Ritchie M., Rudan I., Salomaa V., Samani N.J., Saramies J., Sarzynski M.A., Schwarz P.E.H., Sebert S., Sever P., Shuldiner A.R., Sinisalo J., Steinthorsdottir V., Stolk R.P., Tardif J.-C., Tonjes A., Tremblay A., Tremoli E., Virtamo J., Vohl M.-C., Amouyel P., Asselbergs F.W., Assimes T.L., Bochud M., Boehm B.O., Boerwinkle E., Bottinger E.P., Bouchard C., Cauchi S., Chambers J.C., Chanock S.J., Cooper R.S., De Bakker P.I.W., Dedoussis G., Ferrucci L., Franks P.W., Froguel P., Groop L.C., Haiman C.A., Hamsten A., Hayes M.G., Hui J., Hunter D.J., Hveem K., Jukema J.W., Kaplan R.C., Kivimaki M., Kuh D., Laakso M., Liu Y., Martin N.G., Marz W., Melbye M., Moebus S., Munroe P.B., Njolstad I., Oostra B.A., Palmer C.N.A., Pedersen N.L., Perola M., Perusse L., Peters U., Powell J.E., Power C., Quertermous T., Rauramaa R., Reinmaa E., Ridker P.M., Rivadeneira F., Rotter J.I., Saaristo T.E., Saleheen D., Schlessinger D., Slagboom P.E., Snieder H., Spector T.D., Strauch K., Stumvoll M., Tuomilehto J., Uusitupa M., Van Der Harst P., Volzke H., Walker M., Wareham N.J., Watkins H., Wichmann H.-E., Wilson J.F., Zanen P., Deloukas P., Heid I.M., Lindgren C.M., Mohlke K.L., Speliotes E.K., Thorsteinsdottir U., Barroso I., Fox C.S., North K.E., Strachan D.P., Beckmann J.S., Berndt S.I., Boehnke M., Borecki I.B., McCarthy M.I., Metspalu A., Stefansson K., Uitterlinden A.G., Van Duijn C.M., Franke L., Willer C.J., Price A.L., Lettre G., Loos R.J.F., Weedon M.N., Ingelsson E., O'Connell J.R., Abecasis G.R., Chasman D.I., Goddard M.E., Visscher P.M., Hirschhorn J.N., and Frayling T.M.
Subjects: Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Electronic Medical Records and Genomics (eMEMERGEGE) Consortium, Medizin, Genome-wide association study, Adult, Analysis of Variance, Body Height/genetics, European Continental Ancestry Group/genetics, Genetic Variation/genetics, Genetics, Population, Genome-Wide Association Study/methods, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics, heritability, 0302 clinical medicine, Genome-wide, SNPS, snps, Genetics & Heredity, ddc:616, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, variants, GENETIC-VARIATION, Biological Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], body height, genetic-variation, Life Sciences & Biomedicine, Single Nucleotide/genetics, Human, European Continental Ancestry Group, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, NO, complex traits, 03 medical and health sciences, Genetic variation, heritability, adult, height, Polymorphism, Human height, PAGEGE Consortium, education, Gene, VLAG, 030304 developmental biology, Global Nutrition, Wereldvoeding, genome-wide association study, Science & Technology, Whites, Oligonucleotide Array Sequence Analysi, MUTATIONS, COMPLEX TRAITS, ta1184, Klinisk medicin, population genetics, Genetic Variation, Heritability, ta3121, mutations, Genetic architecture, Body Height, genetic variation, MIGen Consortium, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Clinical Medicine, 030217 neurology & neurosurgery, height, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract: Item does not contain fulltext Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Published: 2014

49. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018)

Author: Evangelou, E, Warren, HR, Mosen-Ansorena, D, Mifsud, B, Pazoki, R, Gao, H, Ntritsos, G, Dimou, N, Cabrera, CP, Karaman, I, Fu, LN, Evangelou, M, Witkowska, K, Tzanis, E, Hellwege, JN, Giri, A, Edwards, DRV, Sun, YV, Cho, K, Gaziano, JM, Wilson, PWF, Tsao, PS, Kovesdy, CP, Esko, T, Magi, R, Milani, L, Almgren, P, Boutin, T, Debette, S, Ding, J, Giulianini, F, Holliday, EG, Jackson, AU, Li-Gao, R, Lin, W-Y, Luan, J, Mangino, M, Oldmeadow, C, Prins, BP, Qian, Y, Sargurupremraj, M, Shah, N, Surendran, P, Theriault, S, Verweij, N, Willems, SM, Zhao, J-H, Amouyel, P, Connell, J, De Mutsert, R, Doney, ASF, Farrall, M, Menni, C, Morris, AD, Noordam, R, Pare, G, Poulter, NR, Shields, DC, Stanton, A, Thom, S, Abecasis, G, Amin, N, Arking, DE, Ayers, KL, Barbieri, CM, Batini, C, Bis, JC, Blake, T, Bochud, M, Boehnke, M, Boerwinkle, E, Boomsma, DI, Bottinger, EP, Braund, PS, Brumat, M, Campbell, A, Campbell, H, Chakravarti, A, Chambers, JC, Chauhan, G, Ciullo, M, Cocca, M, Collins, F, Cordell, HJ, Davies, G, De Borst, MH, De Geus, EJ, Deary, IJ, Deelen, J, Del Greco, FM, Demirkale, CY, Dorr, M, Ehret, GB, Elosua, R, Enroth, S, Erzurumluoglu, AM, Ferreira, T, Franberg, M, Franco, OH, Gandin, I, Gasparini, P, Giedraitis, V, Gieger, C, Girotto, G, Goel, A, Gow, AJ, Gudnason, V, Guo, X, Gyllensten, U, Hamsten, A, Harris, TB, Harris, SE, Hartman, CA, Havulinna, AS, Hicks, AA, Hofer, E, Hofman, A, Hottenga, J-J, Huffman, JE, Hwang, S-J, Ingelsson, E, James, A, Jansen, R, Jarvelin, M-R, Joehanes, R, Johansson, A, Johnson, AD, Joshi, PK, Jousilahti, P, Jukema, JW, Jula, A, Kahonen, M, Kathiresan, S, Keavney, BD, Khaw, K-T, Knekt, P, Knight, J, Kolcic, I, Kooner, JS, Koskinen, S, Kristiansson, K, Kutalik, Z, Laan, M, Larson, M, Launer, LJ, Lehne, B, Lehtimaki, T, Liewald, DCM, Lin, L, Lind, L, Lindgren, CM, Liu, Y, Loos, RJF, Lopez, LM, Lu, Y, Lyytikainen, L-P, Mahajan, A, Mamasoula, C, Marrugat, J, Marten, J, Milaneschi, Y, Morgan, A, Morris, AP, Morrison, AC, Munson, PJ, Nalls, MA, Nandakumar, P, Nelson, CP, Niiranen, T, Nolte, IM, Nutile, T, Oldehinkel, AJ, Oostra, BA, O'Reilly, PF, Org, E, Padmanabhan, S, Palmas, W, Palotie, A, Pattie, A, Penninx, BWJH, Perola, M, Peters, A, Polasek, O, Pramstaller, PP, Quang, TN, Raitakari, OT, Ren, M, Rettig, R, Rice, K, Ridker, PM, Ried, JS, Riese, H, Ripatti, S, Robino, A, Rose, LM, Rotter, JI, Rudan, I, Ruggiero, D, Saba, Y, Sala, CF, Salomaa, V, Samani, NJ, Sarin, A-P, Schmidt, R, Schmidt, H, Shrine, N, Siscovick, D, Smith, AV, Snieder, H, Sober, S, Sorice, R, Starr, JM, Stott, DJ, Strachan, DP, Strawbridge, RJ, Sundstrom, J, Swertz, MA, Taylor, KD, Teumer, A, Tobin, MD, Tomaszewski, M, Toniolo, D, Traglia, M, Trompet, S, Tuomilehto, J, Tzourio, C, Uitterlinden, AG, Vaez, A, Van der Most, PJ, Van Duijn, CM, Vergnaud, A-C, Verwoert, GC, Vitart, V, Volker, U, Vollenweider, P, Vuckovic, D, Watkins, H, Wild, SH, Willemsen, G, Wilson, JF, Wright, AF, Yao, J, Zemunik, T, Zhang, W, Attia, JR, Butterworth, AS, Chasman, DI, Conen, D, Cucca, F, Danesh, J, Hayward, C, Howson, JMM, Laakso, M, Lakatta, EG, Langenberg, C, Melander, O, Mook-Kanamori, DO, Palmer, CNA, Risch, L, Scott, RA, Scott, RJ, Sever, P, Spector, TD, Van der Harst, P, Wareham, NJ, Zeggini, E, Levy, D, Munroe, PB, Newton-Cheh, C, Brown, MJ, Metspalu, A, Hung, AM, O'Donnell, CJ, Edwards, TL, Psaty, BM, Tzoulaki, I, Barnes, MR, Wain, LV, Elliott, P, and Caulfield, MJ
Subjects: Genetics & Heredity, Science & Technology, Million Veteran Program, 06 Biological Sciences, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Developmental Biology
Abstract: Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0205-x, published online 17 September 2018.
Published: 2018

50. Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study

Author: Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaëlsson, K, Markus, HS, Malik, R, Chauhan, G, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, RM, Benavente, OR, Bevan, S, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, and Rothwell, PM
Subjects: Stroke, Neurology & Neurosurgery, Intracranial Embolism, Humans, Calcium, Magnesium, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Brain Ischemia
Abstract: © 2019 American Academy of Neurology. ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2018

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