367 results on '"Marcus E Kleber"'
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2. rs41291957 controls miR‐143 and miR‐145 expression and impacts coronary artery disease risk
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Ignacio Fernando Hall, Montserrat Climent, Chiara Viviani Anselmi, Laura Papa, Vinicius Tragante, Luca Lambroia, Floriana Maria Farina, Marcus E Kleber, Winfried März, Carlo Biguori, Gianluigi Condorelli, and Leonardo Elia
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atherosclerosis ,coronary artery disease ,genetics ,microRNA ,SNP ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract The role of single nucleotide polymorphisms (SNPs) in the etiopathogenesis of cardiovascular diseases is well known. The effect of SNPs on disease predisposition has been established not only for protein coding genes but also for genes encoding microRNAs (miRNAs). The miR‐143/145 cluster is smooth muscle cell‐specific and implicated in the pathogenesis of atherosclerosis. Whether SNPs within the genomic sequence of the miR‐143/145 cluster are involved in cardiovascular disease development is not known. We thus searched annotated sequence databases for possible SNPs associated with miR‐143/145. We identified one SNP, rs41291957 (G > A), located −91 bp from the mature miR‐143 sequence, as the nearest genetic variation to this miRNA cluster, with a minor allele frequency > 10%. In silico and in vitro approaches determined that rs41291957 (A) upregulates miR‐143 and miR‐145, modulating phenotypic switching of vascular smooth cells towards a differentiated/contractile phenotype. Finally, we analysed association between rs41291957 and CAD in two cohorts of patients, finding that the SNP was a protective factor. In conclusion, our study links a genetic variation to a pathological outcome through involvement of miRNAs.
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- 2021
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3. Associations of autozygosity with a broad range of human phenotypes
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David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson
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Science - Abstract
Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.
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- 2019
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4. Are soluble ST2 levels influenced by vitamin D and/or the seasons?
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Vito Francic, Martin Keppel, Verena Schwetz, Christian Trummer, Marlene Pandis, Valentin Borzan, Martin R Grübler, Nicolas D Verheyen, Marcus E Kleber, Graciela Delgado, Angela P Moissl, Benjamin Dieplinger, Winfried März, Andreas Tomaschitz, Stefan Pilz, and Barbara Obermayer-Pietsch
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soluble ST2 ,seasonality ,vitamin D ,biomarker ,cardiovascular disease ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Objective: Cardiovascular disease manifestation and several associated surrogate markers, such as vitamin D, have shown substantial seasonal variation. A promising cardiovascular biomarker, soluble ST2 (sST2), has not been investigated in this regard – we therefore determined if systemic levels of sST2 are affected by seasonality and/or vitamin D in order to investigate their clinical interrelation and usability. Design: sST2 levels were measured in two cohorts involving hypertensive patients at cardiovascular risk, the Styrian Vitamin D Hypertension Trial (study A; RCT design, 8 weeks 2800 IU cholecalciferol daily) and the Ludwigshafen Risk and Cardiovascular Health Study (LURIC; study B; cross-sectional design). Methods: The effects of a vitamin D intervention on sST2 levels were determined in study A using ANCOVA, while seasonality of sST2 levels was determined in study B using ANOVA. Results: The concentrations of sST2 remained unchanged by a vitamin D intervention in study A, with a mean treatment effect (95% confidence interval) of 0.1 (−0.6 to 0.8) ng/mL; P = 0.761), despite a rise in 25(OH)D (11.3 (9.2–13.5) ng/mL; P < 0.001) compared to placebo. In study B, seasonal variations were present in 25(OH)D levels in men and women with or without heart failure (P < 0.001 for all subgroups), while sST2 levels remained unaffected by the seasons in all subgroups. Conclusions: Our study provides the first evidence that systemic sST2 levels are not interrelated with vitamin D levels or influenced by the seasons in subjects at cardiovascular risk.
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- 2019
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5. Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.
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Lars Wallentin, Niclas Eriksson, Maciej Olszowka, Tanja B Grammer, Emil Hagström, Claes Held, Marcus E Kleber, Wolfgang Koenig, Winfried März, Ralph A H Stewart, Harvey D White, Mikael Åberg, and Agneta Siegbahn
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Medicine - Abstract
BackgroundCirculating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.Methods and findingsThe derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.ConclusionsProfiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.Trial registrationClinicalTrials.gov NCT00799903.
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- 2021
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6. Investigation of gene-gene interactions in cardiac traits and serum fatty acid levels in the LURIC Health Study.
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Jiayan Zhou, Kristin Passero, Nicole E Palmiero, Bertram Müller-Myhsok, Marcus E Kleber, Winfried Maerz, and Molly A Hall
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Medicine ,Science - Abstract
Epistasis analysis elucidates the effects of gene-gene interactions (G×G) between multiple loci for complex traits. However, the large computational demands and the high multiple testing burden impede their discoveries. Here, we illustrate the utilization of two methods, main effect filtering based on individual GWAS results and biological knowledge-based modeling through Biofilter software, to reduce the number of interactions tested among single nucleotide polymorphisms (SNPs) for 15 cardiac-related traits and 14 fatty acids. We performed interaction analyses using the two filtering methods, adjusting for age, sex, body mass index (BMI), waist-hip ratio, and the first three principal components from genetic data, among 2,824 samples from the Ludwigshafen Risk and Cardiovascular (LURIC) Health Study. Using Biofilter, one interaction nearly met Bonferroni significance: an interaction between rs7735781 in XRCC4 and rs10804247 in XRCC5 was identified for venous thrombosis with a Bonferroni-adjusted likelihood ratio test (LRT) p: 0.0627. A total of 57 interactions were identified from main effect filtering for the cardiac traits G×G (10) and fatty acids G×G (47) at Bonferroni-adjusted LRT p < 0.05. For cardiac traits, the top interaction involved SNPs rs1383819 in SNTG1 and rs1493939 (138kb from 5' of SAMD12) with Bonferroni-adjusted LRT p: 0.0228 which was significantly associated with history of arterial hypertension. For fatty acids, the top interaction between rs4839193 in KCND3 and rs10829717 in LOC107984002 with Bonferroni-adjusted LRT p: 2.28×10-5 was associated with 9-trans 12-trans octadecanoic acid, an omega-6 trans fatty acid. The model inflation factor for the interactions under different filtering methods was evaluated from the standard median and the linear regression approach. Here, we applied filtering approaches to identify numerous genetic interactions related to cardiac-related outcomes as potential targets for therapy. The approaches described offer ways to detect epistasis in the complex traits and to improve precision medicine capability.
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- 2020
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7. The association of high-normal international-normalized-ratio (INR) with mortality in patients referred for coronary angiography.
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Graciela E Delgado, Andreas Zirlik, Rudolf Gruber, Thomas Scheffold, Bernhard K Krämer, Winfried März, and Marcus E Kleber
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Medicine ,Science - Abstract
AimsThe international-normalized-ratio (INR) is typically used to monitor patients on warfarin or related oral anticoagulant therapy. The aim of our study was to investigate the association of the INR with mortality in coronary artery disease (CAD) patients not on oral anticoagulant therapy.Methods and resultsBetween 1997 to 2000 the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study enrolled 3316 patients of German ancestry that had been referred for coronary angiography. We excluded patients on coumarin therapy (n = 222) and patients with an INR more than 5 standard deviations (SD) away from the mean (n = 30). During a median follow-up of 9.9 years, 884 patients died, 547 patients from cardiovascular causes. After adjustment for cardiovascular risk factors the INR was associated with all-cause mortality in all patients and the CAD positive group with HRs (95% CI) of 1.14(1.07-1.21) and 1.16(1.09-1.23) per 1-SD increase, respectively. Adjustment for NT-proBNP rendered the association insignificant.ConclusionIn LURIC, the INR was positively associated with mortality in patients with prevalent CAD not on oral anticoagulant therapy as well as in patients without CAD. Adjustment for NT-proBNP abolished the association suggesting clinical or subclinical heart failure strongly contributing to increased INR and higher mortality.
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- 2019
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8. Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.
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Cavin K Ward-Caviness, Paul S de Vries, Kerri L Wiggins, Jennifer E Huffman, Lisa R Yanek, Lawrence F Bielak, Franco Giulianini, Xiuqing Guo, Marcus E Kleber, Tim Kacprowski, Stefan Groß, Astrid Petersman, George Davey Smith, Fernando P Hartwig, Jack Bowden, Gibran Hemani, Martina Müller-Nuraysid, Konstantin Strauch, Wolfgang Koenig, Melanie Waldenberger, Thomas Meitinger, Nathan Pankratz, Eric Boerwinkle, Weihong Tang, Yi-Ping Fu, Andrew D Johnson, Ci Song, Moniek P M de Maat, André G Uitterlinden, Oscar H Franco, Jennifer A Brody, Barbara McKnight, Yii-Der Ida Chen, Bruce M Psaty, Rasika A Mathias, Diane M Becker, Patricia A Peyser, Jennifer A Smith, Suzette J Bielinski, Paul M Ridker, Kent D Taylor, Jie Yao, Russell Tracy, Graciela Delgado, Stella Trompet, Naveed Sattar, J Wouter Jukema, Lewis C Becker, Sharon L R Kardia, Jerome I Rotter, Winfried März, Marcus Dörr, Daniel I Chasman, Abbas Dehghan, Christopher J O'Donnell, Nicholas L Smith, Annette Peters, and Alanna C Morrison
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Medicine ,Science - Abstract
BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and findingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
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- 2019
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9. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.
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Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, Rona J Strawbridge, Clara Podmore, Man Li, Jie Yao, Xueling Sim, Jaeyoung Hong, Audrey Y Chu, Weihua Zhang, Xu Wang, Peng Chen, Nisa M Maruthur, Bianca C Porneala, Stephen J Sharp, Yucheng Jia, Edmond K Kabagambe, Li-Ching Chang, Wei-Min Chen, Cathy E Elks, Daniel S Evans, Qiao Fan, Franco Giulianini, Min Jin Go, Jouke-Jan Hottenga, Yao Hu, Anne U Jackson, Stavroula Kanoni, Young Jin Kim, Marcus E Kleber, Claes Ladenvall, Cecile Lecoeur, Sing-Hui Lim, Yingchang Lu, Anubha Mahajan, Carola Marzi, Mike A Nalls, Pau Navarro, Ilja M Nolte, Lynda M Rose, Denis V Rybin, Serena Sanna, Yuan Shi, Daniel O Stram, Fumihiko Takeuchi, Shu Pei Tan, Peter J van der Most, Jana V Van Vliet-Ostaptchouk, Andrew Wong, Loic Yengo, Wanting Zhao, Anuj Goel, Maria Teresa Martinez Larrad, Dörte Radke, Perttu Salo, Toshiko Tanaka, Erik P A van Iperen, Goncalo Abecasis, Saima Afaq, Behrooz Z Alizadeh, Alain G Bertoni, Amelie Bonnefond, Yvonne Böttcher, Erwin P Bottinger, Harry Campbell, Olga D Carlson, Chien-Hsiun Chen, Yoon Shin Cho, W Timothy Garvey, Christian Gieger, Mark O Goodarzi, Harald Grallert, Anders Hamsten, Catharina A Hartman, Christian Herder, Chao Agnes Hsiung, Jie Huang, Michiya Igase, Masato Isono, Tomohiro Katsuya, Chiea-Chuen Khor, Wieland Kiess, Katsuhiko Kohara, Peter Kovacs, Juyoung Lee, Wen-Jane Lee, Benjamin Lehne, Huaixing Li, Jianjun Liu, Stephane Lobbens, Jian'an Luan, Valeriya Lyssenko, Thomas Meitinger, Tetsuro Miki, Iva Miljkovic, Sanghoon Moon, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Ramaiah Nagaraja, Matthias Nauck, James S Pankow, Ozren Polasek, Inga Prokopenko, Paula S Ramos, Laura Rasmussen-Torvik, Wolfgang Rathmann, Stephen S Rich, Neil R Robertson, Michael Roden, Ronan Roussel, Igor Rudan, Robert A Scott, William R Scott, Bengt Sennblad, David S Siscovick, Konstantin Strauch, Liang Sun, Morris Swertz, Salman M Tajuddin, Kent D Taylor, Yik-Ying Teo, Yih Chung Tham, Anke Tönjes, Nicholas J Wareham, Gonneke Willemsen, Tom Wilsgaard, Aroon D Hingorani, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Josephine Egan, Luigi Ferrucci, G Kees Hovingh, Antti Jula, Mika Kivimaki, Meena Kumari, Inger Njølstad, Colin N A Palmer, Manuel Serrano Ríos, Michael Stumvoll, Hugh Watkins, Tin Aung, Matthias Blüher, Michael Boehnke, Dorret I Boomsma, Stefan R Bornstein, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Yduan-Tsong Chen, Ching-Yu Cheng, Francesco Cucca, Eco J C de Geus, Panos Deloukas, Michele K Evans, Myriam Fornage, Yechiel Friedlander, Philippe Froguel, Leif Groop, Myron D Gross, Tamara B Harris, Caroline Hayward, Chew-Kiat Heng, Erik Ingelsson, Norihiro Kato, Bong-Jo Kim, Woon-Puay Koh, Jaspal S Kooner, Antje Körner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Xu Lin, Yongmei Liu, Ruth J F Loos, Patrik K E Magnusson, Winfried März, Mark I McCarthy, Albertine J Oldehinkel, Ken K Ong, Nancy L Pedersen, Mark A Pereira, Annette Peters, Paul M Ridker, Charumathi Sabanayagam, Michele Sale, Danish Saleheen, Juha Saltevo, Peter Eh Schwarz, Wayne H H Sheu, Harold Snieder, Timothy D Spector, Yasuharu Tabara, Jaakko Tuomilehto, Rob M van Dam, James G Wilson, James F Wilson, Bruce H R Wolffenbuttel, Tien Yin Wong, Jer-Yuarn Wu, Jian-Min Yuan, Alan B Zonderman, Nicole Soranzo, Xiuqing Guo, David J Roberts, Jose C Florez, Robert Sladek, Josée Dupuis, Andrew P Morris, E-Shyong Tai, Elizabeth Selvin, Jerome I Rotter, Claudia Langenberg, Inês Barroso, and James B Meigs
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Medicine - Abstract
BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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10. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.
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Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
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Genetics ,QH426-470 - Abstract
[This corrects the article DOI: 10.1371/journal.pgen.1006528.].
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11. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.
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Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
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Genetics ,QH426-470 - Abstract
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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12. Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium.
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Martin Gaksch, Rolf Jorde, Guri Grimnes, Ragnar Joakimsen, Henrik Schirmer, Tom Wilsgaard, Ellisiv B Mathiesen, Inger Njølstad, Maja-Lisa Løchen, Winfried März, Marcus E Kleber, Andreas Tomaschitz, Martin Grübler, Gudny Eiriksdottir, Elias F Gudmundsson, Tamara B Harris, Mary F Cotch, Thor Aspelund, Vilmundur Gudnason, Femke Rutters, Joline W J Beulens, Esther van 't Riet, Giel Nijpels, Jacqueline M Dekker, Diana Grove-Laugesen, Lars Rejnmark, Markus A Busch, Gert B M Mensink, Christa Scheidt-Nave, Michael Thamm, Karin M A Swart, Ingeborg A Brouwer, Paul Lips, Natasja M van Schoor, Christopher T Sempos, Ramón A Durazo-Arvizu, Zuzana Škrabáková, Kirsten G Dowling, Kevin D Cashman, Mairead Kiely, and Stefan Pilz
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Medicine ,Science - Abstract
BACKGROUND:Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. METHODS:In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. FINDINGS:We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and
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13. Neutrophil gelatinase-associated lipocalin levels are U-shaped in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study-Impact for mortality.
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Rainer P Woitas, Hubert Scharnagl, Marcus E Kleber, Graciela E Delgado, Tanja B Grammer, Martin Pichler, Bernhard K Krämer, Winfried März, and Tatjana Stojakovic
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Medicine ,Science - Abstract
INTRODUCTION:Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein released by damaged renal tubular cells and mature neutrophils. It is elevated in kidney injury, but also in patients with coronary artery disease (CAD) and myocardial infarction. We investigated the prognostic value of NGAL for total and cardiovascular mortality in patients undergoing coronary angiography without history of renal insufficiency at inclusion into the study. PARTICIPANTS:The LURIC study is an ongoing prospective cohort study of patients referred for coronary angiography and is designed to evaluate determinants of cardiovascular health. RESULTS:NGAL was determined in plasma of 2997 persons (mean age: 62.7 years; 69.7% men) with a follow up for 10 years. 2358 patients suffered from CAD and 638 did not-these patients served as controls. Stable CAD was found in 1408 and unstable CAD in 950 patients. Death rate from cardiovascular events and all causes was highest in patients within the 4th quartile of NGAL (≥56 ng/ml, p
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14. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.
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Paul S de Vries, Maria Sabater-Lleal, Daniel I Chasman, Stella Trompet, Tarunveer S Ahluwalia, Alexander Teumer, Marcus E Kleber, Ming-Huei Chen, Jie Jin Wang, John R Attia, Riccardo E Marioni, Maristella Steri, Lu-Chen Weng, Rene Pool, Vera Grossmann, Jennifer A Brody, Cristina Venturini, Toshiko Tanaka, Lynda M Rose, Christopher Oldmeadow, Johanna Mazur, Saonli Basu, Mattias Frånberg, Qiong Yang, Symen Ligthart, Jouke J Hottenga, Ann Rumley, Antonella Mulas, Anton J M de Craen, Anne Grotevendt, Kent D Taylor, Graciela E Delgado, Annette Kifley, Lorna M Lopez, Tina L Berentzen, Massimo Mangino, Stefania Bandinelli, Alanna C Morrison, Anders Hamsten, Geoffrey Tofler, Moniek P M de Maat, Harmen H M Draisma, Gordon D Lowe, Magdalena Zoledziewska, Naveed Sattar, Karl J Lackner, Uwe Völker, Barbara McKnight, Jie Huang, Elizabeth G Holliday, Mark A McEvoy, John M Starr, Pirro G Hysi, Dena G Hernandez, Weihua Guan, Fernando Rivadeneira, Wendy L McArdle, P Eline Slagboom, Tanja Zeller, Bruce M Psaty, André G Uitterlinden, Eco J C de Geus, David J Stott, Harald Binder, Albert Hofman, Oscar H Franco, Jerome I Rotter, Luigi Ferrucci, Tim D Spector, Ian J Deary, Winfried März, Andreas Greinacher, Philipp S Wild, Francesco Cucca, Dorret I Boomsma, Hugh Watkins, Weihong Tang, Paul M Ridker, Jan W Jukema, Rodney J Scott, Paul Mitchell, Torben Hansen, Christopher J O'Donnell, Nicholas L Smith, David P Strachan, and Abbas Dehghan
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Medicine ,Science - Abstract
An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
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15. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
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Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
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Genetics ,QH426-470 - Abstract
[This corrects the article DOI: 10.1371/journal.pgen.1005378.].
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- 2016
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16. PCSK9 Plasma Concentrations Are Independent of GFR and Do Not Predict Cardiovascular Events in Patients with Decreased GFR.
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Kyrill S Rogacev, Gunnar H Heine, Günther Silbernagel, Marcus E Kleber, Sarah Seiler, Insa Emrich, Simone Lennartz, Christian Werner, Adam M Zawada, Danilo Fliser, Michael Böhm, Winfried März, Hubert Scharnagl, and Ulrich Laufs
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Medicine ,Science - Abstract
BACKGROUND:Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored. METHODS:Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths. RESULTS:PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results. CONCLUSION:In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.
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- 2016
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17. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
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Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
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Genetics ,QH426-470 - Abstract
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR
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- 2015
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18. Investigating the associations of self-rated health: heart rate variability is more strongly associated than inflammatory and other frequently used biomarkers in a cross sectional occupational sample.
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Marc N Jarczok, Marcus E Kleber, Julian Koenig, Adrian Loerbroks, Raphael M Herr, Kristina Hoffmann, Joachim E Fischer, Yael Benyamini, and Julian F Thayer
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Medicine ,Science - Abstract
The present study aimed to investigate the possible mechanisms linking a single-item measure of global self-rated health (SRH) with morbidity by comparing the association strengths between SRH with markers of autonomic nervous system (ANS) function, inflammation, blood glucose and blood lipids. Cross-sectional comprehensive health-check data of 3947 working adults (age 42±11) was used to calculate logistic regressions, partial correlations and compare correlation strength using Olkins Z. Adjusted logistic regression models showed a negative association between SRH (higher values indicating worse health) and measures of heart rate variability (HRV). Glycemic markers were positively associated with poor SRH. No adjusted association was found with inflammatory markers, BP or lipids. In both unadjusted and adjusted linear models Pearson's correlation strength was significantly higher between SRH with HRV measures compared to SRH with other biomarkers. This is the first study investigating the association of ANS function and SRH. We showed that a global measure of SRH is associated with HRV, and that all measures of ANS function were significantly more strongly associated with SRH than any other biomarker. The current study supports the hypothesis that the extent of brain-body communication, as indexed by HRV, is associated with self-rated health.
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- 2015
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19. Glycerophospholipid and sphingolipid species and mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.
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Alexander Sigruener, Marcus E Kleber, Susanne Heimerl, Gerhard Liebisch, Gerd Schmitz, and Winfried Maerz
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Medicine ,Science - Abstract
Vascular and metabolic diseases cause half of total mortality in Europe. New prognostic markers would provide a valuable tool to improve outcome. First evidence supports the usefulness of plasma lipid species as easily accessible markers for certain diseases. Here we analyzed association of plasma lipid species with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Plasma lipid species were quantified by electrospray ionization tandem mass spectrometry and Cox proportional hazards regression was applied to assess their association with total and cardiovascular mortality. Overall no differences were detected between total and cardiovascular mortality. Highly polyunsaturated phosphatidylcholine species together with lysophosphatidylcholine species and long chain saturated sphingomyelin and ceramide species seem to be associated with a protective effect. The predominantly circulating phosphatidylcholine-based as well as phosphatidylethanolamine-based ether species and phosphatidylethanolamine species were positively associated with total and cardiovascular mortality. Saturated and monounsaturated phosphatidylcholine species, especially phosphatidylcholine 32∶0 (most probably dipalmitoyl-phosphatidylcholine) and palmitate containing sphingomyelin and ceramide species showed together with 24∶1 containing sphingomyelin and ceramide species strongest positive association with mortality. A quotient of the sums of the six most protective species and the six species with the strongest positive mortality association indicated an almost 3-fold increased risk of mortality, which was higher than the hazard ratio for known risk factors in our cohort. Plasma lipid species levels and especially ratios of certain species may be valuable prognostic marker for cardiovascular and total mortality.
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- 2014
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20. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
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Joshua C Randall, Thomas W Winkler, Zoltán Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, Andre Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, DIAGRAM Consortium, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Jarvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M Van der Klauw, Jana V Van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, and Iris M Heid
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Genetics ,QH426-470 - Abstract
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR
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- 2013
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21. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.
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Karani S Vimaleswaran, Diane J Berry, Chen Lu, Emmi Tikkanen, Stefan Pilz, Linda T Hiraki, Jason D Cooper, Zari Dastani, Rui Li, Denise K Houston, Andrew R Wood, Karl Michaëlsson, Liesbeth Vandenput, Lina Zgaga, Laura M Yerges-Armstrong, Mark I McCarthy, Josée Dupuis, Marika Kaakinen, Marcus E Kleber, Karen Jameson, Nigel Arden, Olli Raitakari, Jorma Viikari, Kurt K Lohman, Luigi Ferrucci, Håkan Melhus, Erik Ingelsson, Liisa Byberg, Lars Lind, Mattias Lorentzon, Veikko Salomaa, Harry Campbell, Malcolm Dunlop, Braxton D Mitchell, Karl-Heinz Herzig, Anneli Pouta, Anna-Liisa Hartikainen, Genetic Investigation of Anthropometric Traits-GIANT Consortium, Elizabeth A Streeten, Evropi Theodoratou, Antti Jula, Nicholas J Wareham, Claes Ohlsson, Timothy M Frayling, Stephen B Kritchevsky, Timothy D Spector, J Brent Richards, Terho Lehtimäki, Willem H Ouwehand, Peter Kraft, Cyrus Cooper, Winfried März, Chris Power, Ruth J F Loos, Thomas J Wang, Marjo-Riitta Järvelin, John C Whittaker, Aroon D Hingorani, and Elina Hyppönen
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Medicine - Abstract
BackgroundObesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.Methods and findingsWe used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).ConclusionsOn the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
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- 2013
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22. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.
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Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Mace, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, SUNLIGHT Consortium, GEFOS Consortium, Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polasek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, and Murielle Bochud
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Genetics ,QH426-470 - Abstract
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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- 2013
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23. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
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Robert Clarke, Derrick A Bennett, Sarah Parish, Petra Verhoef, Mariska Dötsch-Klerk, Mark Lathrop, Peng Xu, Børge G Nordestgaard, Hilma Holm, Jemma C Hopewell, Danish Saleheen, Toshihiro Tanaka, Sonia S Anand, John C Chambers, Marcus E Kleber, Willem H Ouwehand, Yoshiji Yamada, Clara Elbers, Bas Peters, Alexandre F R Stewart, Muredach M Reilly, Barbara Thorand, Salim Yusuf, James C Engert, Themistocles L Assimes, Jaspal Kooner, John Danesh, Hugh Watkins, Nilesh J Samani, Rory Collins, Richard Peto, and MTHFR Studies Collaborative Group
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Medicine - Abstract
BackgroundModerately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so "Mendelian randomization" studies using this variant as an instrumental variable could help test causality.Methods and findingsNineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04-1.21) in the 14 larger studies (those with variance of log ORConclusionsThe CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
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- 2012
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24. A variant in the ABO gene explains the variation in soluble E-selectin levels-results from dense genotyping in two independent populations.
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Mahir Karakas, Jens Baumert, Marcus E Kleber, Barbara Thorand, Dhayana Dallmeier, Günther Silbernagel, Tanja B Grammer, Wolfgang Rottbauer, Christa Meisinger, Thomas Illig, Winfried März, and Wolfgang Koenig
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Medicine ,Science - Abstract
BackgroundElevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.Methodology/ principal findingsData of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of -0.37 ng/ml (p = 1.87×10(-103)) in KORA and -0.35 ng/ml (p = 5.11×10(-84)) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.Conclusions/ significanceOur findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.
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- 2012
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25. Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.
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Carola Marzi, Eva Albrecht, Pirro G Hysi, Vasiliki Lagou, Melanie Waldenberger, Anke Tönjes, Inga Prokopenko, Katharina Heim, Hannah Blackburn, Janina S Ried, Marcus E Kleber, Massimo Mangino, Barbara Thorand, Annette Peters, Christopher J Hammond, Harald Grallert, Bernhard O Boehm, Peter Kovacs, Ludwig Geistlinger, Holger Prokisch, Bernhard R Winkelmann, Tim D Spector, H-Erich Wichmann, Michael Stumvoll, Nicole Soranzo, Winfried März, Wolfgang Koenig, Thomas Illig, and Christian Gieger
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Genetics ,QH426-470 - Abstract
Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20×10(-111)) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22×10(-11)) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins.
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- 2010
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26. Machine Learning Models Predict the Need of Amputation and/or Peripheral Artery Revascularization in Hypertensive Patients Within 7-Years Follow-Up.
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Konstantina Tsarapatsani, Antonis I. Sakellarios, Vassilis D. Tsakanikas, Hans J. Trampisch, Henrik Rudolf, Nikolaos S. Tachos, Marcus E. Kleber, Winfried März, and Dimitrios I. Fotiadis
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- 2023
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27. Machine Learning Models Predict Fatal Myocardial Infarction Within 10-Years Follow-Up Utilizing Explainable AI.
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Konstantina Tsarapatsani, Antonis I. Sakellarios, Vasilis D. Tsakanikas, Marcus E. Kleber, Winfried März, and Dimitrios I. Fotiadis
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- 2023
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28. Machine Learning Models for Cardiovascular Disease Events Prediction.
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Konstantina Tsarapatsani, Antonis I. Sakellarios, Vasileios C. Pezoulas, Vassilis D. Tsakanikas, Marcus E. Kleber, Winfried März, Lampros K. Michalis, and Dimitrios I. Fotiadis
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- 2022
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29. Machine Learning Models to Predict Myocardial Infarction Within 10-Years Follow-up of Cardiovascular Disease Progression.
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Konstantina Tsarapatsani, Antonis I. Sakellarios, Vasileios C. Pezoulas, Vasilis D. Tsakanikas, George K. Matsopoulos, Winfried März, Marcus E. Kleber, and Dimitrios I. Fotiadis
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- 2022
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30. A hybrid data harmonization workflow using word embeddings for the interlinking of heterogeneous cross-domain clinical data structures.
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Vasileios C. Pezoulas, Antonis I. Sakellarios, Marcus E. Kleber, Jos A. Bosch, Sander W. Van der Laan, Femke Lamers, Terho Lehtimäki, Winfried März, and Dimitrios I. Fotiadis
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- 2021
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31. Phenome-wide Association Studies on Cardiovascular Health and Fatty Acids Considering PhenotypeQuality Control Practices for Epidemiological Data.
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Kristin Passero, Xi He, Jiayan Zhou, Bertram Müller-Myhsok, Marcus E. Kleber, Winfried März, and Molly A. Hall
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- 2020
32. Haptoglobin polymorphism, vitamin E and mortality: the Ludwigshafen Risk and Cardiovascular Health Study
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Wilfried Renner, Winfried März, Graciela E Delgado, Marcus E Kleber, Angela P Moissl, Brigitte M Winklhofer-Roob, Bernhard K Krämer, Tanja Langsenlehner, Thomas B Dschietzig, and Franz P Armbruster
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Nutritional diseases. Deficiency diseases ,RC620-627 - Abstract
Objective In humans, haptoglobin (Hp) exists in two allelic forms, Hp1 and Hp2, that differ significantly in their ability to protect the organism from oxidative stress. It has been proposed that in patients with diabetes mellitus carriers of the Hp2-2 genotype may benefit from vitamin E supplementation. Aim of our study was to investigate if there is evidence regarding a potential interaction between the Hp polymorphism and vitamin E with regard to mortality in individuals at medium-to-high cardiovascular risk with and without diabetes mellitus.Research design and methods Data from 3176 participants of the Ludwigshafen Risk and Cardiovascular Health study, a monocentric hospital-based study of patients referred for coronary angiography, were analysed using Cox proportional hazard regression.Results Participants with the Hp2-2 genotype demonstrated significantly lower Hp levels, while carriers of at least one Hp-2 allele displayed elevated levels of the inflammatory markers high-sensitive C reactive protein and serum amyloid A. No notable differences in comorbidities were observed among the various HP genotype groups. While the HP genotype showed no direct association with mortality, a borderline significant correlation between α-tocopherol plasma concentration and overall mortality was noted. An interaction between vitamin E status and the HP genotype regarding mortality risk was evident, particularly among patients with diabetes mellitus, with a p value of 0.021 for the interaction term. In restricted cubic splice analysis, patients with diabetes mellitus who are carriers of the Hp2-2 genotype seem to benefit from higher γ-tocopherol concentrations whereas for the other genotype groups there was a direct association with mortality risk.Conclusion Particularly in patients with diabetes mellitus we could show a significant interaction of γ-tocopherol plasma concentration and HP genotype. Carriers of the Hp2-2 genotype seemed to benefit from higher plasma concentrations of γ-tocopherol. Further research is warranted to elucidate the underlying mechanisms and potential therapeutic implications in cardiovascular disease management.
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33. DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood
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Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L. McCartney, Alexander Teumer, Jenny van Dongen, Marcus E. Kleber, Dylan Aïssi, Brenton R. Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R. Brown, Ricardo Costeira, Eco J.C. de Geus, Graciela E. Delgado, Dre'Von A. Dobson, Paul Elliott, Hans J. Grabe, Xiuqing Guo, Sarah E. Harris, Jennifer E. Huffman, Sharon L.R. Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E. Marioni, Matthias Nauck, Scott M. Ratliff, Maria Sabater-Lleal, Tim D. Spector, Pierre Suchon, Kent D. Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L. Wiggins, Gonneke Willemsen, Jordana T. Bell, Dorret I. Boomsma, Shelley A. Cole, Simon R. Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I. Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A. Smith, Andrew D. Johnson, Myriam Fornage, Nicholas L. Smith, Alisa S. Wolberg, Alanna C. Morrison, Paul S. de Vries, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Personalized Medicine, AMS - Ageing & Vitality, AMS - Sports, APH - Health Behaviors & Chronic Diseases, and APH - Methodology
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DNA methylation ,Hematology ,genetics [Fibrinogen] ,methods [Genome-Wide Association Study] ,epigenome-wide association study ,Epigenesis, Genetic ,genetics [Inflammation] ,SDG 3 - Good Health and Well-being ,Genetic Loci ,inflammation ,Mendelian randomization ,Humans ,CpG Islands ,ddc:610 ,fibrinogen - Abstract
Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.
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- 2023
34. Loci for insulin processing and secretion provide insight into type 2 diabetes risk
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K. Alaine Broadaway, Xianyong Yin, Alice Williamson, Victoria A. Parsons, Emma P. Wilson, Anne H. Moxley, Swarooparani Vadlamudi, Arushi Varshney, Anne U. Jackson, Vasudha Ahuja, Stefan R. Bornstein, Laura J. Corbin, Graciela E. Delgado, Om P. Dwivedi, Lilian Fernandes Silva, Timothy M. Frayling, Harald Grallert, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Christian Herder, Sandra Herrmann, Kurt Højlund, David A. Hughes, Marcus E. Kleber, Cecilia M. Lindgren, Ching-Ti Liu, Jian’an Luan, Anni Malmberg, Angela P. Moissl, Andrew P. Morris, Nikolaos Perakakis, Annette Peters, John R. Petrie, Michael Roden, Peter E.H. Schwarz, Sapna Sharma, Angela Silveira, Rona J. Strawbridge, Tiinamaija Tuomi, Andrew R. Wood, Peitao Wu, Björn Zethelius, Damiano Baldassarre, Johan G. Eriksson, Tove Fall, Jose C. Florez, Andreas Fritsche, Bruna Gigante, Anders Hamsten, Eero Kajantie, Markku Laakso, Jari Lahti, Deborah A. Lawlor, Lars Lind, Winfried März, James B. Meigs, Johan Sundström, Nicholas J. Timpson, Robert Wagner, Mark Walker, Nicholas J. Wareham, Hugh Watkins, Inês Barroso, Stephen O’Rahilly, Niels Grarup, Stephen CJ. Parker, Michael Boehnke, Claudia Langenberg, Eleanor Wheeler, and Karen L. Mohlke
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Genetics ,ALSPAC ,Genetics (clinical) - Abstract
Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p-value < 5x10-8), which validated 12 previously reported loci for proinsulin and 10 additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher vs. lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait loci (eQTL) data, suggesting candidate genes including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal, but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms predisposing to disease.
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- 2023
35. Polyvascular disease, pulse pressure and mortality
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Babak Yazdani, Marcus E. Kleber, Gökhan Yücel, Graciela E. Delgado, Faeq Husain-Syed, Bernd Krüger, Winfried März, Kay Schwenke, Martin Sigl, and Bernhard K. Krämer
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Cardiology and Cardiovascular Medicine - Abstract
Summary: Background: Peripheral arterial disease (PAD), coronary artery disease (CAD) and carotid stenosis (CS) are robust predictors of mortality. The value of individual vascular beds in polyvascular disease (PVD) to predict mortality in patients with atherosclerotic burden is not clear. Therefore, we have examined the predictive value of PAD, CAD and CS in patients at intermediate to high risk of cardiovascular (CV) disease. Patients and methods: In our retrospective observational study we analyzed baseline data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, a monocentric cohort study of 3316 patients referred to coronary angiography. Results: As the number of atherosclerotic vascular beds increased, the hazard ratios (HRs) for both all-cause mortality and CV mortality significantly increased in a multivariate analysis after adjusting for age, sex, body mass index, diabetes mellitus and estimated glomerular filtration rate, with HRs of 1.36 (95%CI: 1.11–1.68), 2.56 (95%CI: 2.01–3.26), 2.84 (95%CI: 1.93–4.17) and 1.56 (95%CI: 1.19–2.06), 2.70 (95%CI: 1.97–3.72), 3.50 (95%CI: 2.19–5.62), respectively. The combination of PAD with either CAD or CS was associated with higher HRs for all-cause (HR 2.81 and 7.53, respectively) and CV (HRs 2.80 and 6.03, respectively) mortality compared with the combination of CAD and CS (HRs 1.94 and 2.43, respectively). The presence of PVD was associated with higher age, systolic blood pressure, pulse pressure (PP; a marker of vascular stiffness), former smoking and inversely with lower eGFR. Conclusions: We show that as the number of atherosclerotic vascular beds increases, all-cause and CV mortality rates increase in parallel. Simultaneous prevalence of PAD is associated with significantly higher all-cause and CV mortality rates compared with CS coexistence. Furthermore, increasing atherosclerotic load may contribute to vascular stiffness and impaired renal function.
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- 2022
36. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
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Richard A. Jensen, Denis Rybin, Jaakko Tuomilehto, Reedik Mägi, Inga Prokopenko, Jeffrey R. O'Connell, Marcus E. Kleber, Han Chen, Geoffrey A. Walford, Allan Linnenberg, Anke Tönjes, Francis S. Collins, Sonsoles Morcillo, Gemma Rojo-Martínez, Kenneth Rice, Jose C. Florez, Leif Groop, Manuel Serrano-Ríos, Josée Dupuis, Alisa K. Manning, Peter Kovacs, Torben Jørgensen, Graciela E. Delgado, Alena Stančáková, Hans-Ulrich Häring, Claudia Langenberg, Joshua P. Lewis, Norbert Stefan, Markku Laakso, Torben Hansen, Bruce M. Psaty, Jian'an Luan, Michael Stumvoll, Mark O. Goodarzi, Robert A. Scott, Oluf Pedersen, Ching-Ti Liu, Michael N. Weedon, Michael Boehnke, Ulf Smith, David S. Siscovick, Aaron Leong, Weijia Xie, James B. Meigs, Claes Landenvall, Anne U. Jackson, Joseph M. Zmuda, Mary L. Biggs, Jerome I. Rotter, Federico Soriguer, Winfried März, Zhongyang Zhang, May E. Montasser, Arturo Corbatón-Anchuelo, J M Gómez-Zumaquero, Günther Silbernagel, Kristine Færch, Karen L. Mohlke, Heikki A. Koistinen, Yii-Der Ida Chen, Jaeyoung Hong, Gracia María Martín-Núñez, María Teresa Martínez-Larrad, Emil V. R. Appel, Niels Grarup, Harald Staiger, Johanna Kuusisto, Lars Lind, Nicholas J. Wareham, Andreas Fritsche, Stefan Gustafsson, Andrew P. Morris, Richard N. Bergman, Mark Walker, Cecilia M. Lindgren, Erik Ingelsson, Jorge R. Kizer, Timothy M. Frayling, and Fausto Machicao
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0301 basic medicine ,Male ,Insulin Receptor Substrate Proteins ,Endocrinology, Diabetes and Metabolism ,Locus (genetics) ,Genome-wide association study ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Endocrinology & Metabolism ,Insulin resistance ,Genotype ,Internal Medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic association ,Genetics ,business.industry ,Insulin sensitivity ,Genetics/Genomes/Proteomics/Metabolomics ,11 Medical And Health Sciences ,medicine.disease ,IRS1 ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Chemokines, CC ,Female ,Insulin Resistance ,business ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
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- 2023
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37. Inverse association between apolipoprotein C-II and cardiovascular mortality: role of lipoprotein lipase activity modulation
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Günther Silbernagel, Yan Q Chen, Martin Rief, Marcus E Kleber, Michael M Hoffmann, Tatjana Stojakovic, Andreas Stang, Mark A Sarzynski, Claude Bouchard, Winfried März, Yue-Wei Qian, Hubert Scharnagl, and Robert J Konrad
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Medizin ,Cardiology and Cardiovascular Medicine - Abstract
Aims Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II–mediated LPL activation is unclear. Methods and results ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7–10.7) years. Apolipoprotein C-II–mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)–LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1–LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1–LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody. Conclusion The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1–LPL enzymatic activity.
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- 2023
38. Galectin-3 and Blood Group: Binding Properties, Effects on Plasma Levels, and Consequences for Prognostic Performance
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Carolin Pozder, Elles M. Screever, A. Rogier van der Velde, Herman H. Silljé, Janne Suwijn, Saskia de Rond, Marcus E. Kleber, Graciela Delgado, Jan Jacob Schuringa, Wiek H. van Gilst, Wouter C. Meijers, Winfried März, Rudolf A. de Boer, Faculteit Medische Wetenschappen/UMCG, Cardiovascular Centre (CVC), Stem Cell Aging Leukemia and Lymphoma (SALL), and Cardiology
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Inorganic Chemistry ,Organic Chemistry ,galectin-3 ,biomarker ,blood group ,General Medicine ,prognosis ,Physical and Theoretical Chemistry ,von Willebrand factor ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Previous studies have reported an association between ABO type blood group and cardiovascular (CV) events and outcomes. The precise mechanisms underpinning this striking observation remain unknown, although differences in von Willebrand factor (VWF) plasma levels have been proposed as an explanation. Recently, galectin-3 was identified as an endogenous ligand of VWF and red blood cells (RBCs) and, therefore, we aimed to explore the role of galectin-3 in different blood groups. Two in vitro assays were used to assess the binding capacity of galectin-3 to RBCs and VWF in different blood groups. Additionally, plasma levels of galectin-3 were measured in different blood groups in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2571 patients hospitalized for coronary angiography) and validated in a community-based cohort of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (3552 participants). To determine the prognostic value of galectin-3 in different blood groups, logistic regression and cox regression models were used with all-cause mortality as the primary outcome. First, we demonstrated that galectin-3 has a higher binding capacity for RBCs and VWF in non-O blood groups, compared to blood group O. Additionally, LURIC patients with non-O blood groups had substantially lower plasma levels of galectin-3 (15.0, 14.9, and 14.0 μg/L in blood groups A, B, and AB, respectively, compared to 17.1 μg/L in blood group O, p < 0.0001). Finally, the independent prognostic value of galectin-3 for all-cause mortality showed a non-significant trend towards higher mortality in non-O blood groups. Although plasma galectin-3 levels are lower in non-O blood groups, the prognostic value of galectin-3 is also present in subjects with a non-O blood group. We conclude that physical interaction between galectin-3 and blood group epitopes may modulate galectin-3, which may affect its performance as a biomarker and its biological activity.
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- 2023
39. Platelet Reactivity and Cardiovascular Mortality Risk in the LURIC Study
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Martin Berger, Alexander Dressel, Marcus E. Kleber, Winfried März, Peter Hellstern, Nikolaus Marx, and Katharina Schütt
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platelet reactivity ,Fibrinogen-binding ,CD62p ,cardiovascular mortality ,CD63 ,General Medicine - Abstract
Journal of Clinical Medicine 12(5), 1913 (2023). doi:10.3390/jcm12051913 special issue: "Topical Collection "Cardiovascular Disease: Risk Factors, Comorbidities, and Prevention" / Editor: Prof. Dr. François Roubille, Guest Editor", Published by MDPI, Basel
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- 2023
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40. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
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Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, HUSLAB, Epigenetics of Complex Diseases and Traits, Department of Medicine, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Faculty Common Matters (Faculty of Social Sciences), Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Tampere University, Primary Health Care, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Epidemiology and Data Science, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Lee Kong Chian School of Medicine (LKCMedicine), Peloso, Gina M [0000-0002-5355-8636], Apollo - University of Cambridge Repository, Epidemiology, Department of Marketing Management, Erasmus MC other, Radiology & Nuclear Medicine, Kanoni, Stavroula, Graham, Sarah E, Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg J M, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, Qiping, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian'An, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achillea, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Flori, Mcdaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthia, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Munz, Matthia, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Luka, Scholz, Marku, Galesloot, Tessel E, Bradfield, Jonathan P, Ruotsalainen, Sanni E, Daw, Ewarwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Vazquez-Moreno, Miguel, Feitosa, Mary F, Wojczynski, Mary K, Wang, Zhe, Preuss, Michael H, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Tsao, Noah L, Verma, Anurag, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L, Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlo, Lyssenko, Valeriya, Nongmaithem, Suraj S, Bayyana, Swati, Stringham, Heather M, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R H J, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B, Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, van der Laan, Sander W, Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R, Doumatey, Ayo P, Adeyemo, Adebowale A, Lee, Jong Young, Petersen, Eva R B, Nielsen, Aneta A, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J, Kim, Eung Kweon, Adams, Hieab H H, Ikram, M Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline W J, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Loui, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Clae, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Zimmermann, Martina E, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L R, Peyser, Patricia A, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Böger, Carsten A, Jung, Bettina, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morri, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B, Samani, Nilesh J, Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lar, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Hunt, Steven C, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Mercader, Josep M, Costanzo, Maria C, Jang, Dongkeun, Burtt, Noël P, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, Eshyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, Mcknight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, Mccarthy, Mark I, Palmer, Colin N A, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M 't, Elders, Petra J M, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J F, Province, Michael A, Parra, Esteban J, Cruz, Miguel, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Rotimi, Charles N, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F A, Kiemeney, Lambertus A L M, de Graaf, Jacqueline, Loeffler, Marku, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O, van Dijk, Ko Willem, Watkins, Hugh, Strachan, David P, Grarup, Niel, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik K E, Boomsma, Dorret I, Willemsen, Allegonda H M, Cupples, Ladrienne, van Meurs, Joyce B J, Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, Hazelhurst, Scott, Ramsay, Michèle, North, Kari E, Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Baras, Ari, Justice, Anne E, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charle, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A, Trembath, Richard C, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M Geoffrey, Ritchie, Marylyn D, Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, Yeugene, Ho, Yuk-Lam, Lynch, Julie A, Rader, Daniel J, Tsao, Philip S, Chang, Kyong-Mi, Cho, Kelly, O'Donnell, Christopher J, Gaziano, John M, Wilson, Peter W F, Frayling, Timothy M, Hirschhorn, Joel N, Kathiresan, Sekar, Mohlke, Karen L, Sun, Yan V, Morris, Andrew P, Boehnke, Michael, Brown, Christopher D, Natarajan, Pradeep, Deloukas, Pano, Willer, Cristen J, Assimes, Themistocles L, and Peloso, Gina M
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Genome-wide association study ,Medizin ,Polymorphism, Single Nucleotide ,Humans ,Genome-Wide Association Study ,Genetic Predisposition to Disease ,Sex Characteristics ,Phenotype ,Lipids/genetics ,Genetic Pleiotropy ,Cholesterol ,GWAS ,Genetics ,Lipids ,Genetic ,SDG 3 - Good Health and Well-being ,Medicine [Science] ,112 Statistics and probability ,Medicinsk genetik ,Genome-wide Association Study ,Gwas ,1184 Genetics, developmental biology, physiology ,3126 Surgery, anesthesiology, intensive care, radiology ,3142 Public health care science, environmental and occupational health ,3141 Health care science ,FOS: Biological sciences ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,3111 Biomedicine ,Medical Genetics - Abstract
Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756
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- 2022
41. Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2
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Joachim Thiery, Graciela E. Delgado, Stefanie M. Hauck, Angela Silveira, Ferdinand M. van’t Hooft, Elizabeth Theusch, Markus Scholz, Jesper R. Gådin, Holger Kirsten, Marcus E. Kleber, Ralph Burkhardt, Markus Loeffler, Ronald M. Krauss, Hubert Scharnagl, Janne Pott, and Winfried März
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Genetics ,Candidate gene ,Apolipoprotein B ,PCSK9 ,Membrane Proteins ,Locus (genetics) ,Mendelian Randomization Analysis ,Lipid metabolism ,Genome-wide association study ,Cholesterol, LDL ,Coronary Artery Disease ,General Medicine ,Biology ,Receptors, LDL ,biology.protein ,Humans ,Kexin ,Proprotein Convertase 9 ,Molecular Biology ,Genetics (clinical) ,Apolipoproteins B ,Genome-Wide Association Study - Abstract
Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades low-density lipoprotein (LDL) receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by low-density lipoprotein–cholesterol (LDL–C). Methods and Results We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12 721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD. Conclusion Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.
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- 2021
42. Lipid profiles of patients with manifest coronary versus peripheral atherosclerosis – Is there a difference?
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Winfried März, Andreas Leiherer, Antti Jylhä, Axel Mündlein, Heinz Drexel, Christoph H. Säly, Eva Maria Brandtner, Marcus E. Kleber, Arthur Mader, Alexander Vonbank, Peter Fraunberger, Mitja Lääperi, Jörn F Dopheide, Reijo Laaksonen, and Hana Ramadani
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medicine.medical_specialty ,Ceramide ,Apolipoprotein B ,Lipoproteins ,Blood lipids ,CAD ,Inflammation ,Coronary Artery Disease ,Ceramides ,Coronary artery disease ,Peripheral Arterial Disease ,chemistry.chemical_compound ,Risk Factors ,Internal medicine ,Internal Medicine ,medicine ,Humans ,cardiovascular diseases ,biology ,Cholesterol ,business.industry ,Atherosclerosis ,medicine.disease ,Lipids ,Diabetes Mellitus, Type 2 ,chemistry ,Phosphatidylcholines ,biology.protein ,Cardiology ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,business ,Lipoprotein - Abstract
Aims Peripheral arterial disease (PAD) and coronary artery disease (CAD) are both caused by atherosclerosis. Serum lipids and lipoproteins are predictive of the development of atherosclerosis but it is not clear if they differ in the two manifestations PAD and CAD. We tested whether a more detailed characterization of the lipid and lipoprotein patterns of PAD and CAD allows a clear differentiation between the two atherosclerotic phenotypes. Methods A cohort of 274 statin-naive patients with either newly diagnosed imaging proven PAD (n = 89) or stable CAD (n = 185) was characterized using NMR- and LC-MS/MS-based advanced lipid and lipoprotein analysis. An independent cohort of 1239 patients with PAD and CAD was used for validation. Results We found a significant difference in markers of inflammation as well as ceramide and phosphatidylcholine levels between PAD and CAD patients. In contrast, basic lipid markers including total cholesterol, low density lipoprotein cholesterol, high density lipoprotein-cholesterol, lipoprotein (a) or detailed lipoprotein profiles did not differ significantly between PAD and CAD patients. Applying ratios and scores derived from ceramides and phosphatidylcholines further improved the discrimination between PAD and CAD. These significant differences were independent from body composition, from the status of smoking or T2DM, and also from apolipoprotein C-III and other inflammatory parameters which were different between CAD and PAD. Conclusion The present study clearly suggests that PAD and CAD differ in terms of their ceramide- and phosphatidylcholine-based lipid pattern but not in lipoprotein characteristics. This article is protected by copyright. All rights reserved.
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- 2021
43. Methylation status of
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Saara, Marttila, Hely, Tamminen, Sonja, Rajić, Pashupati P, Mishra, Terho, Lehtimäki, Olli, Raitakari, Mika, Kähönen, Laura, Kananen, Juulia, Jylhävä, Sara, Hägg, Thomas, Delerue, Annette, Peters, Melanie, Waldenberger, Marcus E, Kleber, Winfried, März, Riitta, Luoto, Jani, Raitanen, Elina, Sillanpää, Eija K, Laakkonen, Aino, Heikkinen, Miina, Ollikainen, and Emma, Raitoharju
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Humans ,Twins, Monozygotic ,DNA Methylation - Published
- 2022
44. The renin-angiotensin-aldosterone system, neurohumoral axis and cardiovascular mortality in LURIC
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Babak Yazdani, Graciela E. Delgado, Marcus E. Kleber, Gökhan Yücel, Faeq Husain‐Syed, Thomas D. Kraemer, Jan Jochims, Jan Leipe, Winfried März, and Bernhard K. Krämer
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Renin-Angiotensin System ,Angiotensins ,Endocrinology, Diabetes and Metabolism ,Hypertension ,Internal Medicine ,Humans ,Cardiology and Cardiovascular Medicine - Abstract
Although neurohormones and Renin-Angiotensin-Aldosterone-System (RAAS) components are important predictors of cardiovascular mortality (CVM), their importance for predicting outcomes in patients with/without RAAS-blockers and different degrees of arterial stiffness is less understood. We therefore analyzed long-term data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study in 3316 patients subdivided according to pulse pressure (PP) and RAAS-blocker use. Patients on RAAS-inhibition had higher renin and noradrenaline, lower aldosterone and aldosterone/renin quotient (ARQ). Renin and noradrenaline significantly predicted CVM in patients without RAAS-blocker (HR = 1.17, 1.15) and in patients receiving angiotensin-converting-enzyme (ACE) inhibitors (HR = 1.17, 1.29), whereas aldosterone predicted CVM only in patients receiving ACE-inhibitors (HR = 1.13). CVM was predicted independently from PP by renin, noradrenaline and angiotensin II. Independently from RAAS inhibition renin decreased and ARQs increased with rising PP. Furthermore, noradrenaline increased with PP, but only without ACE-inhibition. The HR for CVM in the ACE-inhibitor group were 1.29, 1.28, 1.29 for renin in the first, second and third PP quartiles and 1.22, and 1.19 for aldosterone in the second and fourth quartile. Furthermore, we showed that noradrenaline predicts CVM in all PP quartiles in patients with ACE-inhibition. In the RAAS-blocker-free group, the HR for renin for CVM were 1.36 and 1.18 in the third and fourth PP quartiles, but neither aldosterone nor noradrenaline were predictive for CVM within the PP quartiles. Renin and noradrenaline are strong predictors of CVM regardless of RAAS blockade, whereas aldosterone is predictive only in the ACE-inhibitor group. Catecholamines but not renin are associated with rising PP.
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- 2022
45. Independent Effects of Kidney Function and Cholesterol Efflux on Cardiovascular Mortality
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Andreas Ritsch, Monika Hunjadi, Tatjana Stojakovic, Jürgen E. Scherberich, Günther Silbernagel, Hubert Scharnagl, Graciela E. Delgado, Marcus E. Kleber, and Winfried März
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single nucleotide polymorphism ,cardiovascular risk ,cholesterol efflux capacity ,high-density lipoprotein ,kidney function ,uromodulin ,Medicine (miscellaneous) ,General Biochemistry, Genetics and Molecular Biology - Abstract
Background: Impaired renal function is associated with cardiovascular and all-cause mortality. In the general population, HDL-cholesterol is associated with cardiovascular events, which is not true in patients with chronic kidney disease (CKD). This has been attributed to abnormal HDL function in CKD. Methods: In this study, we analyzed the association of genetic markers for kidney function with cholesterol efflux capacity as one of the major HDL functions, as well as with cardiovascular mortality, in 2469 patients of the Ludwigshafen Risk and Cardiovascular Health Study who all underwent coronary angiography. Results: A genetic score of 53 SNPs associated with GRF and the uromodulin SNP rs12917707 were inversely correlated with cholesterol efflux capacity. This was in line with the observed association between cholesterol efflux capacity and kidney function in these patients. Adjustment for eGFR and uromodulin as markers of kidney function did not affect the relationship between cholesterol efflux and cardiovascular mortality. Conclusions: Our data propose the view that cholesterol efflux and kidney function are exerting their effects on cardiovascular mortality via different and independent pathways. Decreased cholesterol efflux may therefore not mediate the effects of impaired kidney function on cardiovascular mortality.
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- 2022
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46. Methylation status of VTRNA2-1/nc886 is stable across human populations, monozygotic twin pairs and in majority of somatic tissues
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Saara Marttila, Hely Tamminen, Sonja Rajić, Pashupati P Mishra, Terho Lehtimäki, Olli Raitakari, Mika Kähönen, Laura Kananen, Juulia Jylhävä, Sara Hägg, Thomas Delerue, Annette Peters, Melanie Waldenberger, Marcus E Kleber, Winfried März, Riitta Luoto, Jani Raitanen, Elina Sillanpää, Eija K Laakkonen, Aino Heikkinen, Miina Ollikainen, and Emma Raitoharju
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Aims and methodsOur aim was to characterise the methylation level of a polymorphically imprinted gene, VTRNA2-1/nc886, in human populations and somatic tissues. We utilised 48 datasets, consisting of >30 different tissues and >30 000 individuals.ResultsWe show that the nc886 methylation status is associated with twin status and ethnic background, but the variation between populations is limited. Monozygotic twin pairs present concordant methylation, while ∼30% of dizygotic twin pairs present discordant methylation in the nc886 locus. The methylation levels of nc886 are uniform across somatic tissues, except in cerebellum and skeletal muscle.ConclusionWe hypothesize that the nc886 imprint is established in the oocyte and that after implantation, the methylation status is stable, excluding a few specific tissues.
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- 2022
47. Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization
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Veerle Dam, N Charlotte Onland-Moret, Stephen Burgess, Maria-Dolores Chirlaque, Sanne A E Peters, Ewoud Schuit, Kaja Tikk, Elisabete Weiderpass, Clare Oliver-Williams, Angela M Wood, Anne Tjønneland, Christina C Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Matthias B Schulze, Antonia Trichopoulou, Pietro Ferrari, Giovanna Masala, Vittorio Krogh, Rosario Tumino, Giuseppe Matullo, Salvatore Panico, Jolanda M A Boer, W M Monique Verschuren, Marit Waaseth, Maria José Sánchez Pérez, Pilar Amiano, Liher Imaz, Conchi Moreno-Iribas, Olle Melander, Sophia Harlid, Maria Nordendahl, Patrik Wennberg, Timothy J Key, Elio Riboli, Carmen Santiuste, Rudolf Kaaks, Verena Katzke, Claudia Langenberg, Nicholas J Wareham, Heribert Schunkert, Jeanette Erdmann, Christina Willenborg, Christian Hengstenberg, Marcus E Kleber, Graciela Delgado, Winfried März, Stavroula Kanoni, George Dedoussis, Panos Deloukas, Majid Nikpay, Ruth McPherson, Markus Scholz, Andrej Teren, Adam S Butterworth, Yvonne T van der Schouw, Dam, Veerle [0000-0002-5982-232X], Onland-Moret, N Charlotte [0000-0002-2360-913X], Burgess, Stephen [0000-0001-5365-8760], Chirlaque, Maria-Dolores [0000-0001-9242-3040], Schuit, Ewoud [0000-0002-9548-3214], Weiderpass, Elisabete [0000-0003-2237-0128], Overvad, Kim [0000-0001-6429-7921], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Trichopoulou, Antonia [0000-0002-7204-6396], Ferrari, Pietro [0000-0001-9358-7338], Masala, Giovanna [0000-0002-5758-9069], Krogh, Vittorio [0000-0003-0122-8624], Panico, Salvatore [0000-0002-5498-8312], Harlid, Sophia [0000-0001-8540-6891], Riboli, Elio [0000-0001-6795-6080], Katzke, Verena [0000-0002-6509-6555], Schunkert, Heribert [0000-0001-6428-3001], Hengstenberg, Christian [0000-0002-8284-2994], Kleber, Marcus E [0000-0003-0663-7275], Deloukas, Panos [0000-0001-9251-070X], Nikpay, Majid [0000-0003-0285-6454], McPherson, Ruth [0000-0002-9087-6107], Scholz, Markus [0000-0002-4059-1779], and Apollo - University of Cambridge Repository
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Male ,MENOPAUSE ,Aging ,IMPACT ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Coronary Disease ,VARIANTS ,Biochemistry ,Polymorphism, Single Nucleotide ,AGE ,Endocrinology ,Mendelian Randomization ,Aging/genetics ,Reproductive aging ,risk factors ,Humans ,cardiovascular diseases ,GENOME-WIDE ASSOCIATION ,coronary heart disease ,Coronary Disease/epidemiology ,RISK ,MORTALITY ,Biochemistry (medical) ,Mendelian Randomization Analysis ,Coronary heart disease ,BIAS ,Risk factors ,reproductive aging ,Genome-Wide Association Study/methods ,Female ,FASTING GLUCOSE ,Genome-Wide Association Study - Abstract
The EPIC-CVD project was supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270, MR/L003120/1), the British Heart Foundation (SP/09/002, RG/08/014, RG13/13/30194), and the UK National Institute of Health Research (to EPIC-CVD). The establishment of the subcohort was supported by the EU Sixth Framework Programme (FP6) (grant LSHM_CT_2006_037197 to the InterAct project) and the Medical Research Council Epidemiology Unit (grants MC_ UU_12015/1 and MC_UU_12015/5). The national EPIC cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy) and MIUR "Dipartimenti di Eccellenza"(Project D15D18000410001) to the Department of Medical Sciences; Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); and Cancer Research UK, Medical Research Council (United Kingdom). LIFE-Heart is funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by funds of the Free State of Saxony within the framework of the excellence initiative. This work is supported by the Dutch Heart Foundation (2013T083 to V.D.), by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1 to S.A.E.P.), and by a Sir Henry Dale Fellowship jointly funded by the Welcome Trust and the Royal Society (204623/Z/16/Z to S.B.). None of the funding sources had a role in the collection, analysis, and interpretation of the data, nor in the decision to submit the article for publication., Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men., European Commission HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) G0800270 MR/L003120/1 British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), EU Sixth Framework Programme (FP6) LSHM_CT_2006_037197, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_ UU_12015/1 MC_UU_12015/5, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe Federal Ministry of Education & Research (BMBF) Deutsches Krebsforschungszentrum (Germany), Ministry of Health and Social Solidarity (Greece) Stavros Niarchos Foundation (Greece) Hellenic Health Foundation (Greece), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR) MIUR "Dipartimenti di Eccellenza" D15D18000410001, Dutch Ministry of Public Health, Welfare and Sports, LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF) ERC-2009-AdG 232997, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Instituto de Salud Carlos III, Junta de Andalucia, Principality of Asturias, Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society Swedish Scientific Council (Sweden) Regional Government of Skane and Vasterbotten (Sweden), Cancer Research UK UK Research & Innovation (UKRI) Medical Research Council UK (MRC), Leipzig Research Center for Civilization Diseases (LIFE), European Commission, Free State of Saxony, Netherlands Heart Foundation 2013T083, Medical Research Council UK (MRC) MR/P014550/1, Sir Henry Dale Fellowship - Welcome Trust 204623/Z/16/Z, Sir Henry Dale Fellowship - Royal Society 204623/Z/16/Z
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- 2022
48. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations
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Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center
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Hemostasis ,genome-wide association study ,genetic pleiotropy ,Hematology ,Polymorphism, Single Nucleotide ,Hemostatics ,blood coagulation ,cardiovascular diseases ,Phenotype ,Cardiovascular Diseases ,Tissue Plasminogen Activator ,hemostasis ,Humans ,Genetic Predisposition to Disease ,Factor XI ,Genome-Wide Association Study - 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.
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- 2022
49. Genome-wide association study of circulating interleukin 6 levels identifies novel loci
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Martina Müller-Nurasyid, Jerome I. Rotter, David M. Evans, John P. Kemp, Emelia J. Benjamin, Graciela E. Delgado, Vilmundur Gudnason, Ann Hammarstedt, Panos Deloukas, Aroon D. Hingorani, Riccardo E. Marioni, David Stacey, Jenny van Dongen, Eric Boerwinkle, Joachim Heinrich, Yongmei Liu, S. Goya Wannamethee, Delilah Zabaneh, Braxton D. Mitchell, Marie Standl, Jackie F. Price, Maria G. Stathopoulou, Yoav Ben-Shlomo, Joris Deelen, Eero Kajantie, Mohammadreza Abdollahi, Christie M. Ballantyne, Johan G. Eriksson, Ilkka Seppälä, Elnaz Naderi, Barbara J. Jefferis, Richard W Morris, Nicholas J. Timpson, George Dedoussis, Sirpa Jalkanen, Mika Kivimäki, Perminder S. Sachdev, Diana van Heemst, Melanie Waldenberger, Gaurav Singhal, Elisabeth Thiering, Olli T. Raitakari, Anders Hamsten, Zoltán Kutalik, L. Bain, Eco J. C. de Geus, Tarunveer S. Ahluwalia, Yuri Milaneschi, Hubert Scharnagl, Juan P. Casas, Georg Homuth, Claes Ohlsson, Abbas Dehghan, Nicola J. Armstrong, Behrooz Z. Alizadeh, Terho Lehtimäki, Steve E. Humphries, Naveed Sattar, Bram P. Prins, Peter Rossing, Sophie Visvikis-Siest, Joana A. Revez, Ilja M. Nolte, Stella Trompet, Harold Snieder, Marian Beekman, Diana Marek, Beate St Pourcain, Thorkild I. A. Sørensen, Silvia Naitza, Karen A. Mather, Uwe Völker, Eline Slagboom, Tina Shah, Magdalene C. Jawahar, Jens Baumert, Alexander Teumer, Dorret I. Boomsma, Marcus E. Kleber, Peter Vollenweider, Wolfgang Koenig, Brenda W.J.H. Penninx, Kenneth Rice, Ian J. Deary, Pedro Marques-Vidal, Donna K. Arnett, Eleonora Porcu, Jouke-Jan Hottenga, Maria Sabater-Lleal, Bruce M. Psaty, Matthias Nauck, Dan Mellström, Joel Eriksson, Bernhard T. Baune, Debbie A Lawlor, Catherine Toben, Peter H. Whincup, Toshiko Tanaka, Stavroula Kanoni, Katri Räikkönen, Gonneke Willemsen, Bengt Sennblad, Julian N. Trollor, Yalda Jamshidi, Sarah E. Harris, Jari Lahti, Joshua C. Bis, Peter Durda, Yen Pei C. Chang, Jorgen Engmann, Tom R. Gaunt, Stella Aslibekyan, Anbupalam Thalamuthu, Mary F. Feitosa, Angela Silveira, Tine Jess, Stela McLachlan, J. Wouter Jukema, Chen Lu, Simon P. Mooijaart, Tim D. Spector, Harald Grallert, Winfried März, Alexandros M. Petrelis, Manuel A. R. Ferreira, Meena Kumari, Stochastics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, CHARGE Inflammation Working Group, Epidemiology, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Steno Diabetes Center, University of Copenhagen = Københavns Universitet (KU), University of Groningen [Groningen], Murdoch University, University of Alabama at Birmingham [ Birmingham] (UAB), QIMR Berghofer Medical Research Institute, University College of London [London] (UCL), Helmholtz-Zentrum München (HZM), Leiden University Medical Center (LUMC), University of Bristol [Bristol], University of Washington [Seattle], University of Maryland School of Medicine, University of Maryland System, Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], University of Heidelberg, Medical Faculty, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Sahlgrenska Academy at University of Gothenburg [Göteborg], National Institute for Health and Welfare [Helsinki], University of Helsinki, William Harvey Research Institute, Barts and the London Medical School, University of Queensland [Brisbane], School of Public Health [Boston], Boston University [Boston] (BU), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, University of Edinburgh, Amsterdam UMC, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), Karolinska Institutet [Stockholm], University of Tampere [Finland], Adelaide Medical School [Australia], University of Adelaide, Universität Greifswald - University of Greifswald, University of New South Wales [Sydney] (UNSW), Prince of Wales Hospital, Ludwig-Maximilians-Universität München (LMU), Baylor College of Medicine (BCM), Baylor University, Boston University School of Medicine (BUSM), VA Boston Healthcare System, Harokopio University of Athens, Max planck Institute for Biology of Ageing [Cologne], Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, University of Turku, St George's, University of London, Statens Serum Institut [Copenhagen], Medical Faculty [Mannheim], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Johannes Gutenberg - Universität Mainz (JGU), Vrije Universiteit Medical Centre (VUMC), British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Medical University Graz, Uppsala Universitet [Uppsala], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Kentucky, Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Maryland [Baltimore], Queen Mary University of London (QMUL), University of Iceland [Reykjavik], Ludwig Maximilian University [Munich] (LMU), Melbourne School of Population and Global Health [Melbourne], University of Melbourne, Deutsches Herzzentrum München (DHM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Ulm (UUlm), University of Essex, Greifswald University Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), King‘s College London, University of Cambridge [UK] (CAM), Harbor UCLA Medical Center [Torrance, Ca.], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Human Genome Sequencing Center [Houston] (HGSC), Baylor University-Baylor University, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, HUS Children and Adolescents, Lastentautien yksikkö, Children's Hospital, Clinicum, Department of Bacteriology and Immunology, Department of Public Health, Department of Psychology and Logopedics, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Doctoral Programme in Human Behaviour, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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AcademicSubjects/SCI01140 ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,030204 cardiovascular system & hematology ,DISEASE ,Pathogenesis ,Cohort Studies ,0302 clinical medicine ,cytokine ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,Association Studies Article ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,Genetics ,0303 health sciences ,ARCHITECTURE ,CHRONIC INFLAMMATION ,1184 Genetics, developmental biology, physiology ,General Medicine ,RECEPTOR IL-6R GENE ,C-REACTIVE PROTEIN ,hla-drb1 gene ,3. Good health ,Medical genetics ,Medical Genetics ,chromosomes ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,European Continental Ancestry Group ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,anti-inflammatory agents ,White People ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,Interleukin 6 ,Molecular Biology ,Medicinsk genetik ,030304 developmental biology ,PRODUCE IL-6 ,Interleukin-6 ,Chromosome ,Receptors, Interleukin-6 ,RHEUMATOID-ARTHRITIS ,Interleukin 1 Receptor Antagonist Protein ,Gene Expression Regulation ,Genetic Loci ,CELLS ,biology.protein ,1182 Biochemistry, cell and molecular biology ,Human genome ,3111 Biomedicine ,Genome-Wide Association Study ,HLA-DRB1 Chains ,Interleukin-1 - 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.
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- 2021
50. Association of branched-chain amino acids with mortality-the Ludwigshafen Risk and Cardiovascular Health (LURIC) study
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Angela P. Moissl, Stefan Lorkowski, Andreas Meinitzer, Stefan Pilz, Hubert Scharnagl, Graciela E. Delgado, Marcus E. Kleber, Bernhard K. Krämer, Burkert Pieske, Martin R. Grübler, Helmut Brussee, Dirk von Lewinski, Hermann Toplak, Astrid Fahrleitner-Pammer, Winfried März, and Andreas Tomaschitz
- Subjects
Multidisciplinary ,Article - Abstract
Branched-chain amino acids (BCAAs) are effectors of metabolic diseases, but their impact on mortality is largely unknown. We investigated the association of BCAA with risk factors and mortality in 2,236 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study using linear and Cox regression. Adiponectin, hemoglobin, C-peptide, hemoglobin A(1c), and homoarginine showed the strongest association with BCAA concentration (all p
- Published
- 2023
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