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1. Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD: A Simulation Study From DA VINCI

Author

Vallejo-Vaz, Antonio J., Bray, Sarah, Villa, Guillermo, Brandts, Julia, Kiru, Gaia, Murphy, Jennifer, Banach, Maciej, De Servi, Stefano, Gaita, Dan, Gouni-Berthold, Ioanna, Kees Hovingh, G., Jozwiak, Jacek J., Jukema, J. Wouter, Gabor Kiss, Robert, Kownator, Serge, Iversen, Helle K., Maher, Vincent, Masana, Luis, Parkhomenko, Alexander, Peeters, André, Clifford, Piers, Raslova, Katarina, Siostrzonek, Peter, Romeo, Stefano, Tousoulis, Dimitrios, Vlachopoulos, Charalambos, Vrablik, Michal, Catapano, Alberico L., Poulter, Neil R., and Ray, Kausik K.

Published
2023
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2. Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

Author

Stroes, Erik S, Thompson, Paul D, Corsini, Alberto, Vladutiu, Georgirene D, Raal, Frederick J, Ray, Kausik K, Roden, Michael, Stein, Evan, Tokgözoğlu, Lale, Nordestgaard, Børge G, Bruckert, Eric, De Backer, Guy, Krauss, Ronald M, Laufs, Ulrich, Santos, Raul D, Hegele, Robert A, Hovingh, G Kees, Leiter, Lawrence A, Mach, Francois, März, Winfried, Newman, Connie B, Wiklund, Olov, Jacobson, Terry A, Catapano, Alberico L, Chapman, M John, Ginsberg, Henry N, Stroes, Erik, John Chapman, M, de Backer, Guy, Kees Hovingh, G, and Leiter, Lawrence

Subjects
Clinical Research, Cardiovascular, Atherosclerosis, 2.1 Biological and endogenous factors, Aetiology, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Cholesterol Ester Transfer Proteins, Complementary Therapies, Consensus, Creatine Kinase, Diet, Genetic Predisposition to Disease, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypolipidemic Agents, Mitochondria, Muscle, Mitochondrial Diseases, Muscular Diseases, Proprotein Convertase 9, Proprotein Convertases, Risk Factors, Serine Endopeptidases, European Atherosclerosis Society Consensus Panel, Cholesterol, Consensus statement, Lipids, Mitochondrial, Muscle symptoms, Myalgia, Myopathy, Statin, Statin intolerance, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Published
2015

3. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, Iris, Trompet, Stella, Deshmukh, Harshal A, Barnes, Michael R, Li, Xiaohui, Warren, Helen R, Chasman, Daniel I, Zhou, Kaixin, Arsenault, Benoit J, Donnelly, Louise A, Wiggins, Kerri L, Avery, Christy L, Griffin, Paula, Feng, QiPing, Taylor, Kent D, Li, Guo, Evans, Daniel S, Smith, Albert V, de Keyser, Catherine E, Johnson, Andrew D, de Craen, Anton JM, Stott, David J, Buckley, Brendan M, Ford, Ian, Westendorp, Rudi GJ, Eline Slagboom, P, Sattar, Naveed, Munroe, Patricia B, Sever, Peter, Poulter, Neil, Stanton, Alice, Shields, Denis C, O’Brien, Eoin, Shaw-Hawkins, Sue, Ida Chen, Y-D, Nickerson, Deborah A, Smith, Joshua D, Pierre Dubé, Marie, Matthijs Boekholdt, S, Kees Hovingh, G, Kastelein, John JP, McKeigue, Paul M, Betteridge, John, Neil, Andrew, Durrington, Paul N, Doney, Alex, Carr, Fiona, Morris, Andrew, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Bis, Joshua C, Rice, Kenneth, Smith, Nicholas L, Lumley, Thomas, Whitsel, Eric A, Stürmer, Til, Boerwinkle, Eric, Ngwa, Julius S, O’Donnell, Christopher J, Vasan, Ramachandran S, Wei, Wei-Qi, Wilke, Russell A, Liu, Ching-Ti, Sun, Fangui, Guo, Xiuqing, Heckbert, Susan R, Post, Wendy, Sotoodehnia, Nona, Arnold, Alice M, Stafford, Jeanette M, Ding, Jingzhong, Herrington, David M, Kritchevsky, Stephen B, Eiriksdottir, Gudny, Launer, Leonore J, Harris, Tamara B, Chu, Audrey Y, Giulianini, Franco, MacFadyen, Jean G, Barratt, Bryan J, Nyberg, Fredrik, Stricker, Bruno H, Uitterlinden, André G, Hofman, Albert, Rivadeneira, Fernando, Emilsson, Valur, Franco, Oscar H, Ridker, Paul M, Gudnason, Vilmundur, Liu, Yongmei, Denny, Joshua C, Ballantyne, Christie M, Rotter, Jerome I, Adrienne Cupples, L, Psaty, Bruce M, Palmer, Colin NA, Tardif, Jean-Claude, Colhoun, Helen M, and Hitman, Graham

Subjects
Genetics, Atherosclerosis, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Cholesterol, LDL, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide, Welcome Trust Case Control Consortium
Abstract

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Published
2014

5. Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia

Author

Ibrahim, Shirin, primary, van Rooij, Jeroen, additional, Verkerk, Annemieke J.M.H., additional, de Vries, Jard, additional, Zuurbier, Linda, additional, Defesche, Joep, additional, Peter, Jorge, additional, Schonck, Willemijn A.M., additional, Sedaghati-Khayat, Bahar, additional, Kees Hovingh, G., additional, Uitterlinden, André G., additional, Stroes, Erik S.G., additional, and Reeskamp, Laurens F., additional

Published
2023
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6. Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia

Author

Ibrahim, Shirin, van Rooij, Jeroen, Verkerk, Annemieke J.M.H., de Vries, Jard, Zuurbier, Linda, Defesche, Joep, Peter, Jorge, Schonck, Willemijn A.M., Sedaghati-Khayat, Bahar, Kees Hovingh, G., Uitterlinden, André G., Stroes, Erik S.G., Reeskamp, Laurens F., Ibrahim, Shirin, van Rooij, Jeroen, Verkerk, Annemieke J.M.H., de Vries, Jard, Zuurbier, Linda, Defesche, Joep, Peter, Jorge, Schonck, Willemijn A.M., Sedaghati-Khayat, Bahar, Kees Hovingh, G., Uitterlinden, André G., Stroes, Erik S.G., and Reeskamp, Laurens F.

Abstract

BACKGROUND: Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH. METHODS: An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268). RESULTS: The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%).CONCLUSIONS: The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.

Published
2023

7. Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD:A Simulation Study From DA VINCI

Author

Vallejo-Vaz, Antonio J, Bray, Sarah, Villa, Guillermo, Brandts, Julia, Kiru, Gaia, Murphy, Jennifer, Banach, Maciej, De Servi, Stefano, Gaita, Dan, Gouni-Berthold, Ioanna, Kees Hovingh, G., Jozwiak, Jacek J., Jukema, J. Wouter, Gabor Kiss, Robert, Kownator, Serge, Iversen, Helle K., Maher, Vincent, Masana, Luis, Parkhomenko, Alexander, Peeters, André, Clifford, Piers, Raslova, Katarina, Siostrzonek, Peter, Romeo, Stefano, Tousoulis, Dimitrios, Vlachopoulos, Charalambos, Vrablik, Michal, Catapano, Alberico L., Poulter, Neil R., Ray, Kausik K., Vallejo-Vaz, Antonio J, Bray, Sarah, Villa, Guillermo, Brandts, Julia, Kiru, Gaia, Murphy, Jennifer, Banach, Maciej, De Servi, Stefano, Gaita, Dan, Gouni-Berthold, Ioanna, Kees Hovingh, G., Jozwiak, Jacek J., Jukema, J. Wouter, Gabor Kiss, Robert, Kownator, Serge, Iversen, Helle K., Maher, Vincent, Masana, Luis, Parkhomenko, Alexander, Peeters, André, Clifford, Piers, Raslova, Katarina, Siostrzonek, Peter, Romeo, Stefano, Tousoulis, Dimitrios, Vlachopoulos, Charalambos, Vrablik, Michal, Catapano, Alberico L., Poulter, Neil R., and Ray, Kausik K.

Abstract

Purpose: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated. Methods: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated. Results: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81–115) mg/dl and 32% (25–43%), respectively. Median LDL-C reductions of 24 (12–46) and 39 (27–91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7–25%) and 22% (15–32%), respectively, and ARRs of 4% (2–7%) and 6% (4–9%), respectively. Conclusion: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach. Graphical abstract: [Figure not available: see fulltext.]

Published
2023

9. Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town

Author

Regeneron Pharmaceuticals, Fritz Thyssen Foundation, Amsterdam University Fund, Agence Nationale de la Recherche (France), Eusko Jaurlaritza, Blom, Dirk [0000-0003-3965-5912], Benito-Vicente, Asier [0000-0003-1653-1722], Blackhurst, Dee M. [0000-0002-9899-4634], Kees Hovingh, G. [0000-0002-8145-1676], Martín, César [0000-0002-4087-8729], Huijgen, Roeland, Blom, Dirk, Hartgers, Merel L., Chemello, Kevin, Benito-Vicente, Asier, Uribe, Kepa B., Behardien, Zorena, Blackhurst, Dee M., Brice, Brigitte C., Defesche, Joep C., Jong, Annemiek G. de, Jooste, Rosemary J., Solomon, Gabriele A. E., Wolmarans, Karen H., Kees Hovingh, G., Martín, César, Lambert, Gilles, Marais, A. David, Regeneron Pharmaceuticals, Fritz Thyssen Foundation, Amsterdam University Fund, Agence Nationale de la Recherche (France), Eusko Jaurlaritza, Blom, Dirk [0000-0003-3965-5912], Benito-Vicente, Asier [0000-0003-1653-1722], Blackhurst, Dee M. [0000-0002-9899-4634], Kees Hovingh, G. [0000-0002-8145-1676], Martín, César [0000-0002-4087-8729], Huijgen, Roeland, Blom, Dirk, Hartgers, Merel L., Chemello, Kevin, Benito-Vicente, Asier, Uribe, Kepa B., Behardien, Zorena, Blackhurst, Dee M., Brice, Brigitte C., Defesche, Joep C., Jong, Annemiek G. de, Jooste, Rosemary J., Solomon, Gabriele A. E., Wolmarans, Karen H., Kees Hovingh, G., Martín, César, Lambert, Gilles, and Marais, A. David

Abstract

Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.

Published
2021

10. Implications of ACC/AHA versus ESC/EAS LDL-C recommendations for residual risk reduction in ASCVD

Author

Vallejo-Vaz, Antonio J, Bray, Sarah, Villa, Guillermo, Brandts, Julia, Kiru, Gaia, Murphy, Jennifer, Banach, Maciej, De Servi, Stefano, Gaita, Dan, Gouni-Berthold, Ioanna, Kees Hovingh, G, Jozwiak, Jacek J, Jukema, J Wouter, Gabor Kiss, Robert, Kownator, Serge, Iversen, Helle K, Maher, Vincent, Masana, Luis, Parkhomenko, Alexander, Peeters, André, Clifford, Piers, Raslova, Katarina, Siostrzonek, Peter, Romeo, Stefano, Tousoulis, Dimitrios, Vlachopoulos, Charalambos, Vrablik, Michal, Catapano, Alberico L, Poulter, Neil R, Ray, Kausik K, DA VINCI Study Investigators, Experimental Vascular Medicine, Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes

Subjects
Cardiac & Cardiovascular Systems, STATIN THERAPY, EZETIMIBE, ATORVASTATIN, Cardiovascular disease prevention, CARDIOVASCULAR OUTCOMES, DISEASE, Pharmacology (medical), Pharmacology & Pharmacy, LDL-C, METAANALYSIS, Pharmacology, Science & Technology, Lipid-lowering, Statins, DA VINCI Study Investigators, General Medicine, EFFICACY, Cardiovascular risk, SIMVASTATIN, DENSITY-LIPOPROTEIN CHOLESTEROL, Cardiovascular System & Hematology, SAFETY, Atherosclerotic cardiovascular disease, Cardiovascular System & Cardiology, lipids (amino acids, peptides, and proteins), 1115 Pharmacology and Pharmaceutical Sciences, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine
Abstract

Purpose Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (vs. Methods DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of Results Of the 2039 patients, 61% did not achieve LDL-C Conclusion In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach. Graphical abstract

Published
2022

12. Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD: A Simulation Study From DA VINCI

Author

Vallejo-Vaz, A.J. Bray, S. Villa, G. Brandts, J. Kiru, G. Murphy, J. Banach, M. De Servi, S. Gaita, D. Gouni-Berthold, I. Kees Hovingh, G. Jozwiak, J.J. Jukema, J.W. Gabor Kiss, R. Kownator, S. Iversen, H.K. Maher, V. Masana, L. Parkhomenko, A. Peeters, A. Clifford, P. Raslova, K. Siostrzonek, P. Romeo, S. Tousoulis, D. Vlachopoulos, C. Vrablik, M. Catapano, A.L. Poulter, N.R. Ray, K.K. On behalf of the DA VINCI Study Investigators

Abstract

Purpose: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated. Methods: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated. Results: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81–115) mg/dl and 32% (25–43%), respectively. Median LDL-C reductions of 24 (12–46) and 39 (27–91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7–25%) and 22% (15–32%), respectively, and ARRs of 4% (2–7%) and 6% (4–9%), respectively. Conclusion: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach. Graphical abstract: [Figure not available: see fulltext.] © 2022, The Author(s).

Published
2022

13. Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD : A Simulation Study From DA VINCI

Author

Vallejo-Vaz, Antonio J., Bray, Sarah, Kees Hovingh, G., Jozwiak, Jacek J., Jukema, J. Wouter, Gabor Kiss, Robert, Kownator, Serge, Iversen, Helle K., Maher, Vincent, Masana, Luis, Parkhomenko, Alexander, Peeters, André, Villa, Guillermo, Clifford, Piers, Raslova, Katarina, Siostrzonek, Peter, Romeo, Stefano, Tousoulis, Dimitrios, Vlachopoulos, Charalambos, Vrablik, Michal, Catapano, Alberico L., Poulter, Neil R., Ray, Kausik K., Brandts, Julia Maria, Da Vinci Study Investigators, Kiru, Gaia, Murphy, Jennifer, Banach, Maciej, De Servi, Stefano, Gaita, Dan, and Gouni-Berthold, Ioanna

Abstract

Cardiovascular drugs and therapy (2022). doi:10.1007/s10557-022-07343-x, Published by Springer Science + Business Media B.V, Dordrecht [u.a.]

Published
2022
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15. Genetic studies of body mass index yield new insights for obesity biology

Author

Locke, Adam E., Kahali, Bratati, Berndt, Sonja I., Justice, Anne E., Pers, Tune H., Day, Felix R., Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L., Yang, Jian, Croteau-Chonka, Damien C., Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltán, Luan, Jianʼan, Mägi, Reedik, Randall, Joshua C., Winkler, Thomas W., Wood, Andrew R., Workalemahu, Tsegaselassie, Faul, Jessica D., Smith, Jennifer A., Hua Zhao, Jing, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Åsa K., Karjalainen, Juha, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bolton, Jennifer L., Bragg-Gresham, Jennifer L., Buyske, Steven, Demirkan, Ayse, Deng, Guohong, Ehret, Georg B., Feenstra, Bjarke, Feitosa, Mary F., Fischer, Krista, Goel, Anuj, Gong, Jian, Jackson, Anne U., Kanoni, Stavroula, Kleber, Marcus E., Kristiansson, Kati, Lim, Unhee, Lotay, Vaneet, Mangino, Massimo, Mateo Leach, Irene, Medina-Gomez, Carolina, Medland, Sarah E., Nalls, Michael A., Palmer, Cameron D., Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J., Prokopenko, Inga, Shungin, Dmitry, Stančáková, Alena, Strawbridge, Rona J., Ju Sung, Yun, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W., van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V., Wang, Zhaoming, Yengo, Loïc, Zhang, Weihua, Isaacs, Aaron, Albrecht, Eva, Ärnlöv, Johan, Arscott, Gillian M., Attwood, Antony P., Bandinelli, Stefania, Barrett, Amy, Bas, Isabelita N., Bellis, Claire, Bennett, Amanda J., Berne, Christian, Blagieva, Roza, Blüher, Matthias, Böhringer, Stefan, Bonnycastle, Lori L., Böttcher, Yvonne, Boyd, Heather A., Bruinenberg, Marcel, Caspersen, Ida H., Ida Chen, Yii-Der, Clarke, Robert, Warwick Daw, E., de Craen, Anton J. M., Delgado, Graciela, Dimitriou, Maria, Doney, Alex S. F., Eklund, Niina, Estrada, Karol, Eury, Elodie, Folkersen, Lasse, Fraser, Ross M., Garcia, Melissa E., Geller, Frank, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S., Golay, Alain, Goodall, Alison H., Gordon, Scott D., Gorski, Mathias, Grabe, Hans-Jörgen, Grallert, Harald, Grammer, Tanja B., Gräler, Jürgen, Grönberg, Henrik, Groves, Christopher J., Gusto, Gaëlle, Haessler, Jeffrey, Hall, Per, Haller, Toomas, Hallmans, Goran, Hartman, Catharina A., Hassinen, Maija, Hayward, Caroline, Heard-Costa, Nancy L., Helmer, Quinta, Hengstenberg, Christian, Holmen, Oddgeir, Hottenga, Jouke-Jan, James, Alan L., Jeff, Janina M., Johansson, Åsa, Jolley, Jennifer, Juliusdottir, Thorhildur, Kinnunen, Leena, Koenig, Wolfgang, Koskenvuo, Markku, Kratzer, Wolfgang, Laitinen, Jaana, Lamina, Claudia, Leander, Karin, Lee, Nanette R., Lichtner, Peter, Lind, Lars, Lindström, Jaana, Sin Lo, Ken, Lobbens, Stéphane, Lorbeer, Roberto, Lu, Yingchang, Mach, François, Magnusson, Patrik K. E., Mahajan, Anubha, McArdle, Wendy L., McLachlan, Stela, Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Moayyeri, Alireza, Monda, Keri L., Morken, Mario A., Mulas, Antonella, Müller, Gabriele, Müller-Nurasyid, Martina, Musk, Arthur W., Nagaraja, Ramaiah, Nöthen, Markus M., Nolte, Ilja M., Pilz, Stefan, Rayner, Nigel W., Renstrom, Frida, Rettig, Rainer, Ried, Janina S., Ripke, Stephan, Robertson, Neil R., Rose, Lynda M., Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Schumacher, Fredrick R., Scott, William R., Seufferlein, Thomas, Shi, Jianxin, Vernon Smith, Albert, Smolonska, Joanna, Stanton, Alice V., Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stringham, Heather M., Sundström, Johan, Swertz, Morris A., Swift, Amy J., Syvänen, Ann-Christine, Tan, Sian-Tsung, Tayo, Bamidele O., Thorand, Barbara, Thorleifsson, Gudmar, Tyrer, Jonathan P., Uh, Hae-Won, Vandenput, Liesbeth, Verhulst, Frank C., Vermeulen, Sita H., Verweij, Niek, Vonk, Judith M., Waite, Lindsay L., Warren, Helen R., Waterworth, Dawn, Weedon, Michael N., Wilkens, Lynne R., Willenborg, Christina, Wilsgaard, Tom, Wojczynski, Mary K., Wong, Andrew, Wright, Alan F., Zhang, Qunyuan, Brennan, Eoin P., Choi, Murim, Dastani, Zari, Drong, Alexander W., Eriksson, Per, Franco-Cereceda, Anders, Gådin, Jesper R., Gharavi, Ali G., Goddard, Michael E., Handsaker, Robert E., Huang, Jinyan, Karpe, Fredrik, Kathiresan, Sekar, Keildson, Sarah, Kiryluk, Krzysztof, Kubo, Michiaki, Lee, Jong-Young, Liang, Liming, Lifton, Richard P., Ma, Baoshan, McCarroll, Steven A., McKnight, Amy J., Min, Josine L., Moffatt, Miriam F., Montgomery, Grant W., Murabito, Joanne M., Nicholson, George, Nyholt, Dale R., Okada, Yukinori, Perry, John R. B., Dorajoo, Rajkumar, Reinmaa, Eva, Salem, Rany M., Sandholm, Niina, Scott, Robert A., Stolk, Lisette, Takahashi, Atsushi, Tanaka, Toshihiro, vanʼt Hooft, Ferdinand M., Vinkhuyzen, Anna A. E., Westra, Harm-Jan, Zheng, Wei, Zondervan, Krina T., Heath, Andrew C., Arveiler, Dominique, Bakker, Stephan J. L., Beilby, John, Bergman, Richard N., Blangero, John, Bovet, Pascal, Campbell, Harry, Caulfield, Mark J., Cesana, Giancarlo, Chakravarti, Aravinda, Chasman, Daniel I., Chines, Peter S., Collins, Francis S., Crawford, Dana C., Adrienne Cupples, L., Cusi, Daniele, Danesh, John, de Faire, Ulf, den Ruijter, Hester M., Dominiczak, Anna F., Erbel, Raimund, Erdmann, Jeanette, Eriksson, Johan G., Farrall, Martin, Felix, Stephan B., Ferrannini, Ele, Ferrières, Jean, Ford, Ian, Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Gansevoort, Ron T., Gejman, Pablo V., Gieger, Christian, Gottesman, Omri, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Alistair S., Harris, Tamara B., Hattersley, Andrew T., Hicks, Andrew A., Hindorff, Lucia A., Hingorani, Aroon D., Hofman, Albert, Homuth, Georg, Kees Hovingh, G., Humphries, Steve E., Hunt, Steven C., Hyppönen, Elina, Illig, Thomas, Jacobs, Kevin B., Jarvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Johansen, Berit, Jousilahti, Pekka, Wouter Jukema, J., Jula, Antti M., Kaprio, Jaakko, Kastelein, John J. P., Keinanen-Kiukaanniemi, Sirkka M., Kiemeney, Lambertus A., Knekt, Paul, Kooner, Jaspal S., Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T., Kumari, Meena, Kuusisto, Johanna, Lakka, Timo A., Langenberg, Claudia, Le Marchand, Loic, Lehtimäki, Terho, Lyssenko, Valeriya, Männistö, Satu, Marette, André, Matise, Tara C., McKenzie, Colin A., McKnight, Barbara, Moll, Frans L., Morris, Andrew D., Morris, Andrew P., Murray, Jeffrey C., Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J., Ong, Ken K., Madden, Pamela A. F., Pasterkamp, Gerard, Peden, John F., Peters, Annette, Postma, Dirkje S., Pramstaller, Peter P., Price, Jackie F., Qi, Lu, Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Ridker, Paul M., Rioux, John D., Ritchie, Marylyn D., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Saramies, Jouko, Sarzynski, Mark A., Schunkert, Heribert, Schwarz, Peter E. H., Sever, Peter, Shuldiner, Alan R., Sinisalo, Juha, Stolk, Ronald P., Strauch, Konstantin, Tönjes, Anke, Trégouët, David-Alexandre, Tremblay, Angelo, Tremoli, Elena, Virtamo, Jarmo, Vohl, Marie-Claude, Völker, Uwe, Waeber, Gérard, Willemsen, Gonneke, Witteman, Jacqueline C., Carola Zillikens, M., Adair, Linda S., Amouyel, Philippe, Asselbergs, Folkert W., Assimes, Themistocles L., Bochud, Murielle, Boehm, Bernhard O., Boerwinkle, Eric, Bornstein, Stefan R., Bottinger, Erwin P., Bouchard, Claude, Cauchi, Stéphane, Chambers, John C., Chanock, Stephen J., Cooper, Richard S., de Bakker, Paul I. W., Dedoussis, George, Ferrucci, Luigi, Franks, Paul W., Froguel, Philippe, Groop, Leif C., Haiman, Christopher A., Hamsten, Anders, Hui, Jennie, Hunter, David J., Hveem, Kristian, Kaplan, Robert C., Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, Martin, Nicholas G., März, Winfried, Melbye, Mads, Metspalu, Andres, Moebus, Susanne, Munroe, Patricia B., Njølstad, Inger, Oostra, Ben A., Palmer, Colin N. A., Pedersen, Nancy L., Perola, Markus, Pérusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E., Saleheen, Danish, Sattar, Naveed, Schadt, Eric E., Schlessinger, David, Eline Slagboom, P., Snieder, Harold, Spector, Tim D., Thorsteinsdottir, Unnur, Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, van der Harst, Pim, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wichmann, H-Erich, Wilson, James F., Zanen, Pieter, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Heid, Iris M., OʼConnell, Jeffrey R., Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Abecasis, Gonçalo R., Franke, Lude, Frayling, Timothy M., McCarthy, Mark I., Visscher, Peter M., Scherag, André, Willer, Cristen J., Boehnke, Michael, Mohlke, Karen L., Lindgren, Cecilia M., Beckmann, Jacques S., Barroso, Inês, North, Kari E., Ingelsson, Erik, Hirschhorn, Joel N., Loos, Ruth J. F., and Speliotes, Elizabeth K.

Published
2015
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18. Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy.

Author

Ginsberg, Henry N., Hounslow, Neil J., Yusuke Senko, Hideki Suganami, Bogdanski, Pawel, Ceska, Richard, Kalina, Akos, Libis, Roman A., Supryadkina, Tatiana V., and Kees Hovingh, G.

Subjects
DRUG therapy for hyperlipidemia, PROTEIN metabolism, TRIGLYCERIDES, RESEARCH, ANTILIPEMIC agents, CLOFIBRIC acid, HETEROCYCLIC compounds, RESEARCH methodology, EVALUATION research, COMPARATIVE studies, RANDOMIZED controlled trials, BLIND experiment, STATISTICAL sampling, BUTYRIC acid
Abstract

Objective: High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia.Research Design and Methods: A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12.Results: Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations.Conclusions: Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment. [ABSTRACT FROM AUTHOR]

Published
2022
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19. EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: the DAVINCI study.

Author

Ray, Kausik K., Molemans, Bart, Marieke Schoonen, W., Giovas, Periklis, Bray, Sarah, Kiru, Gaia, Murphy, Jennifer, Banach, Maciej, Servi, Stefano De, Gaita, Dan, Gouni-Berthold, Ioanna, Kees Hovingh, G., Jozwiak, Jacek J., Wouter Jukema, J., Kiss, Robert Gabor, Kownator, Serge, Iversen, Helle K., Maher, Vincent, Masana, Luis, and Parkhomenko, Alexander

Published
2021
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21. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, Iris, Trompet, Stella, Deshmukh, Harshal A., Barnes, Michael R., Li, Xiaohui, Warren, Helen R., Chasman, Daniel I., Zhou, Kaixin, Arsenault, Benoit J., Donnelly, Louise A., Wiggins, Kerri L., Avery, Christy L., Griffin, Paula, Feng, QiPing, Taylor, Kent D., Li, Guo, Evans, Daniel S., Smith, Albert V., de Keyser, Catherine E., Johnson, Andrew D., de Craen, Anton J.M., Stott, David J., Buckley, Brendan M., Ford, Ian, Westendorp, Rudi G. J., Eline Slagboom, P., Sattar, Naveed, Munroe, Patricia B., Sever, Peter, Poulter, Neil, Stanton, Alice, Shields, Denis C., O’Brien, Eoin, Shaw-Hawkins, Sue, Ida Chen, Y.-D., Nickerson, Deborah A., Smith, Joshua D., Pierre Dubé, Marie, Matthijs Boekholdt, S., Kees Hovingh, G., Kastelein, John J.P., McKeigue, Paul M., Betteridge, John, Neil, Andrew, Durrington, Paul N., Doney, Alex, Carr, Fiona, Morris, Andrew, McCarthy, Mark I., Groop, Leif, Ahlqvist, Emma, Bis, Joshua C., Rice, Kenneth, Smith, Nicholas L., Lumley, Thomas, Whitsel, Eric A., Stürmer, Til, Boerwinkle, Eric, Ngwa, Julius S., O’Donnell, Christopher J., Vasan, Ramachandran S., Wei, Wei-Qi, Wilke, Russell A., Liu, Ching-Ti, Sun, Fangui, Guo, Xiuqing, Heckbert, Susan R, Post, Wendy, Sotoodehnia, Nona, Arnold, Alice M., Stafford, Jeanette M., Ding, Jingzhong, Herrington, David M., Kritchevsky, Stephen B., Eiriksdottir, Gudny, Launer, Leonore J., Harris, Tamara B., Chu, Audrey Y., Giulianini, Franco, MacFadyen, Jean G., Barratt, Bryan J., Nyberg, Fredrik, Stricker, Bruno H., Uitterlinden, André G., Hofman, Albert, Rivadeneira, Fernando, Emilsson, Valur, Franco, Oscar H., Ridker, Paul M., Gudnason, Vilmundur, Liu, Yongmei, Denny, Joshua C., Ballantyne, Christie M., Rotter, Jerome I., Adrienne Cupples, L., Psaty, Bruce M., Palmer, Colin N.A., Tardif, Jean-Claude, Colhoun, Helen M., Hitman, Graham, Krauss, Ronald M., Wouter Jukema, J, Caulfield, Mark J., Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M., Bramon, Elvira, Brown, Matthew A., Casas, Juan P., Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S., Mathew, Christopher G., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C.A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E., Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Erasmus MC other, Epidemiology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine

Subjects
Apolipoprotein E, BLOOD, LOCI, General Physics and Astronomy, Genome-wide association study, VARIANTS, 030204 cardiovascular system & hematology, Pharmacology, Bioinformatics, THERAPY, DISEASE, chemistry.chemical_compound, 0302 clinical medicine, GENE-EXPRESSION, 0303 health sciences, Multidisciplinary, biology, 3. Good health, Multidisciplinary Sciences, Meta-analysis, WHOLE-GENOME, Science & Technology - Other Topics, lipids (amino acids, peptides, and proteins), Statin, medicine.drug_class, Endocrinology and Diabetes, Polymorphism, Single Nucleotide, INDUCED MYOPATHY, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Humans, cardiovascular diseases, 030304 developmental biology, Genetic association, Science & Technology, Cholesterol, business.industry, HUMAN PREFRONTAL CORTEX, nutritional and metabolic diseases, General Chemistry, Cholesterol, LDL, A300, chemistry, Pharmacogenetics, biology.protein, PLASMA LIPOPROTEIN(A) LEVELS, Hydroxymethylglutaryl-CoA Reductase Inhibitors, SLCO1B1, business, Genome-Wide Association Study
Abstract

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response., Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.

Published
2016
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22. ODYSSEY FH i and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia

Author

Kastelein, J.J.P., Ginsberg, H.N., Langslet, G., Kees Hovingh, G., Ceska, R., Dufour, R., Blom, D., Civeira, F., Krempf, M., Lorenzato, C., Zhao, J., Pordy, R., Baccara-Dinet, M., Gipe, D.A., Geiger, M.J., and Farnier, M.

Abstract

Aims To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). Met hods and resul ts In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2: 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was =1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; 2 57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; 2 51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C = 1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). Conclusion In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin + other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated.

Published
2016

24. The effect of statins on cardiovascular outcomes by smoking status: A systematic review and meta-analysis of randomized controlled trials

Author

Ursoniu, Sorin, primary, Mikhailidis, Dimitri P., additional, Serban, Maria-Corina, additional, Penson, Peter, additional, Toth, Peter P., additional, Ridker, Paul M., additional, Ray, Kausik K., additional, Kees Hovingh, G., additional, Kastelein, John J., additional, Hernandez, Adrian V., additional, Manson, JoAnn E., additional, Rysz, Jacek, additional, and Banach, Maciej, additional

Published
2017
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26. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Author

Kiezun, Adam, Erdmann, Jeanette, Auer, Paul L., Roberts, Robert, Danesh, John, Farlow, Deborah N., Stitziel, Nathan O., Lange, Leslie A., Goel, Anuj, Shah, Svati H., Zuk, Or, Samani, Nilesh J., DePristo, Mark A., Angelica Merlini, Pier, Saleheen, Danish, Stewart, Alexander F. R., Won, Hong-Hee, Duga, Stefano, Farrall, Martin, Girelli, Domenico, Kraus, William E., Martinelli, Nicola, Epstein, Stephen E., Asselta, Rosanna, Guella, Illaria, Peloso, Gina M., Sivapalaratnam, Suthesh, Kastelein, John J., Kees Hovingh, G., Jørgensen, Anders Berg, Schunkert, Heribert, and Do, Ron

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

Published
2015
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27. Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration

Author

Vallejo-Vaz, Antonio J., Akram, Asif, Rao Kondapally Seshasai, Sreenivasa, Cole, Della, Watts, Gerald F., Kees Hovingh, G., Kastelein, John J. P., Mata, Pedro, Raal, Frederick J., Santos, Raul D., Soran, Handrean, Freiberger, Tomas, Abifadel, Marianne, Aguilar-Salinas, Carlos A., Alnouri, Fahad, Alonso, Rodrigo, Al-Rasadi, Khalid, Banach, Maciej, Bogsrud, Martin P., Bourbon, Mafalda, Bruckert, Eric, Car, Josip, Ceska, Richard, Corral, Pablo, Descamps, Olivier, Dieplinger, Hans, Do, Can T., Durst, Ronen, Ezhov, Marat V., Fras, Zlatko, Gaita, Dan, Gaspar, Isabel M., Genest, Jaques, Harada-Shiba, Mariko, Jiang, Lixin, Kayikcioglu, Meral, Lam, Carolyn S. P., Latkovskis, Gustavs, Laufs, Ulrich, Liberopoulos, Evangelos, Lin, Jie, Lin, Nan, Maher, Vincent, Majano, Nelson, David Marais, A., Maerz, Winfried, Mirrakhimov, Erkin, Miserez, Andre R., Mitchenko, Olena, Nawawi, Hapizah, Nilsson, Lennart, Nordestgaard, Borge G., Paragh, Gyorgy, Petrulioniene, Zaneta, Pojskic, Belma, Reiner, Zeljko, Sahebkar, Amirhossein, Santos, Lourdes E., Schunkert, Heribert, Shehab, Abdullah, Naceur Slimane, M., Stoll, Mario, Su, Ta-Chen, Susekov, Andrey, Tilney, Myra, Tomlinson, Brian, Tselepis, Alexandros D., Vohnout, Branislav, Widen, Elisabeth, Yamashita, Shizuya, Catapano, Alberico L., Ray, Kausik K., Vallejo-Vaz, Antonio J., Akram, Asif, Rao Kondapally Seshasai, Sreenivasa, Cole, Della, Watts, Gerald F., Kees Hovingh, G., Kastelein, John J. P., Mata, Pedro, Raal, Frederick J., Santos, Raul D., Soran, Handrean, Freiberger, Tomas, Abifadel, Marianne, Aguilar-Salinas, Carlos A., Alnouri, Fahad, Alonso, Rodrigo, Al-Rasadi, Khalid, Banach, Maciej, Bogsrud, Martin P., Bourbon, Mafalda, Bruckert, Eric, Car, Josip, Ceska, Richard, Corral, Pablo, Descamps, Olivier, Dieplinger, Hans, Do, Can T., Durst, Ronen, Ezhov, Marat V., Fras, Zlatko, Gaita, Dan, Gaspar, Isabel M., Genest, Jaques, Harada-Shiba, Mariko, Jiang, Lixin, Kayikcioglu, Meral, Lam, Carolyn S. P., Latkovskis, Gustavs, Laufs, Ulrich, Liberopoulos, Evangelos, Lin, Jie, Lin, Nan, Maher, Vincent, Majano, Nelson, David Marais, A., Maerz, Winfried, Mirrakhimov, Erkin, Miserez, Andre R., Mitchenko, Olena, Nawawi, Hapizah, Nilsson, Lennart, Nordestgaard, Borge G., Paragh, Gyorgy, Petrulioniene, Zaneta, Pojskic, Belma, Reiner, Zeljko, Sahebkar, Amirhossein, Santos, Lourdes E., Schunkert, Heribert, Shehab, Abdullah, Naceur Slimane, M., Stoll, Mario, Su, Ta-Chen, Susekov, Andrey, Tilney, Myra, Tomlinson, Brian, Tselepis, Alexandros D., Vohnout, Branislav, Widen, Elisabeth, Yamashita, Shizuya, Catapano, Alberico L., and Ray, Kausik K.

Abstract

Background: The potential for global collaborations to better inform public health policy regarding major non-hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. Methods: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. Conclusions: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients. (C) 2016 Elsevier Ireland Ltd., Funding Agencies|Pfizer Independent Grant for Learning Change [16157823]; Amgen; MSD; Sanofi-Aventis; Latvian State Research Programme BIOMEDICINE; Czech Republic [MZ CR AZV 15-28277A, 16-29084A]

Published
2016
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28. Genetic studies of body mass index yield new insights for obesity biology

Author

Locke, Adam E, Kahali, Bratati, Berndt, Sonja I, Justice, Anne E, Pers, Tune H, Day, Felix R, Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L, Yang, Jian, Croteau-Chonka, Damien C, Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltán, Luan, Jian'an, Mägi, Reedik, Randall, Joshua C, Winkler, Thomas W, Wood, Andrew R, Workalemahu, Tsegaselassie, Faul, Jessica D, Smith, Jennifer A, Hua Zhao, Jing, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Åsa K, Karjalainen, Juha, Schmidt, Ellen M, Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bolton, Jennifer L, Bragg-Gresham, Jennifer L, Buyske, Steven, Demirkan, Ayse, Deng, Guohong, Ehret, Georg B, Feenstra, Bjarke, Feitosa, Mary F, Fischer, Krista, Goel, Anuj, Gong, Jian, Jackson, Anne U, Kanoni, Stavroula, Kleber, Marcus E, Kristiansson, Kati, Lim, Unhee, Lotay, Vaneet, Mangino, Massimo, Mateo Leach, Irene, Medina-Gomez, Carolina, Medland, Sarah E, Nalls, Michael A, Palmer, Cameron D, Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J, Prokopenko, Inga, Shungin, Dmitry, Stančáková, Alena, Strawbridge, Rona J, Ju Sung, Yun, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W, van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V, Wang, Zhaoming, Yengo, Loïc, Zhang, Weihua, Isaacs, Aaron, Albrecht, Eva, Ärnlöv, Johan, Arscott, Gillian M, Attwood, Antony P, Bandinelli, Stefania, Barrett, Amy, Bas, Isabelita N, Bellis, Claire, Bennett, Amanda J, Berne, Christian, Blagieva, Roza, Blüher, Matthias, Böhringer, Stefan, Bonnycastle, Lori L, Böttcher, Yvonne, Boyd, Heather A, Bruinenberg, Marcel, Caspersen, Ida H, Ida Chen, Yii-Der, Clarke, Robert, Warwick Daw, E, de Craen, Anton J M, Delgado, Graciela, Dimitriou, Maria, Doney, Alex S F, Eklund, Niina, Estrada, Karol, Eury, Elodie, Folkersen, Lasse, Fraser, Ross M, Garcia, Melissa E, Geller, Frank, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S, Golay, Alain, Goodall, Alison H, Gordon, Scott D, Gorski, Mathias, Grabe, Hans-Jörgen, Grallert, Harald, Grammer, Tanja B, Gräßler, Jürgen, Grönberg, Henrik, Groves, Christopher J, Gusto, Gaëlle, Haessler, Jeffrey, Hall, Per, Haller, Toomas, Hallmans, Goran, Hartman, Catharina A, Hassinen, Maija, Hayward, Caroline, Heard-Costa, Nancy L, Helmer, Quinta, Hengstenberg, Christian, Holmen, Oddgeir, Hottenga, Jouke-Jan, James, Alan L, Jeff, Janina M, Johansson, Åsa, Jolley, Jennifer, Juliusdottir, Thorhildur, Kinnunen, Leena, Koenig, Wolfgang, Koskenvuo, Markku, Kratzer, Wolfgang, Laitinen, Jaana, Lamina, Claudia, Leander, Karin, Lee, Nanette R, Lichtner, Peter, Lind, Lars, Lindström, Jaana, Sin Lo, Ken, Lobbens, Stéphane, Lorbeer, Roberto, Lu, Yingchang, Mach, François, Magnusson, Patrik K E, Mahajan, Anubha, McArdle, Wendy L, McLachlan, Stela, Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Moayyeri, Alireza, Monda, Keri L, Morken, Mario A, Mulas, Antonella, Müller, Gabriele, Müller-Nurasyid, Martina, Musk, Arthur W, Nagaraja, Ramaiah, Nöthen, Markus M, Nolte, Ilja M, Pilz, Stefan, Rayner, Nigel W, Renstrom, Frida, Rettig, Rainer, Ried, Janina S, Ripke, Stephan, Robertson, Neil R, Rose, Lynda M, Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Schumacher, Fredrick R, Scott, William R, Seufferlein, Thomas, Shi, Jianxin, Vernon Smith, Albert, Smolonska, Joanna, Stanton, Alice V, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stringham, Heather M, Sundström, Johan, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Tayo, Bamidele O, Thorand, Barbara, Thorleifsson, Gudmar, Tyrer, Jonathan P, Uh, Hae-Won, Vandenput, Liesbeth, Verhulst, Frank C, Vermeulen, Sita H, Verweij, Niek, Vonk, Judith M, Waite, Lindsay L, Warren, Helen R, Waterworth, Dawn, Weedon, Michael N, Wilkens, Lynne R, Willenborg, Christina, Wilsgaard, Tom, Wojczynski, Mary K, Wong, Andrew, Wright, Alan F, Zhang, Qunyuan, Brennan, Eoin P, Choi, Murim, Dastani, Zari, Drong, Alexander W, Eriksson, Per, Franco-Cereceda, Anders, Gådin, Jesper R, Gharavi, Ali G, Goddard, Michael E, Handsaker, Robert E, Huang, Jinyan, Karpe, Fredrik, Kathiresan, Sekar, Keildson, Sarah, Kiryluk, Krzysztof, Kubo, Michiaki, Lee, Jong-Young, Liang, Liming, Lifton, Richard P, Ma, Baoshan, McCarroll, Steven A, McKnight, Amy J, Min, Josine L, Moffatt, Miriam F, Montgomery, Grant W, Murabito, Joanne M, Nicholson, George, Nyholt, Dale R, Okada, Yukinori, Perry, John R B, Dorajoo, Rajkumar, Reinmaa, Eva, Salem, Rany M, Sandholm, Niina, Scott, Robert A, Stolk, Lisette, Takahashi, Atsushi, Tanaka, Toshihiro, Van't Hooft, Ferdinand M, Vinkhuyzen, Anna A E, Westra, Harm-Jan, Zheng, Wei, Zondervan, Krina T, Heath, Andrew C, Arveiler, Dominique, Bakker, Stephan J L, Beilby, John, Bergman, Richard N, Blangero, John, Bovet, Pascal, Campbell, Harry, Caulfield, Mark J, Cesana, Giancarlo, Chakravarti, Aravinda, Chasman, Daniel I, Chines, Peter S, Collins, Francis S, Crawford, Dana C, Adrienne Cupples, L, Cusi, Daniele, Danesh, John, de Faire, Ulf, den Ruijter, Hester M, Dominiczak, Anna F, Erbel, Raimund, Erdmann, Jeanette, Eriksson, Johan G, Farrall, Martin, Felix, Stephan B, Ferrannini, Ele, Ferrières, Jean, Ford, Ian, Forouhi, Nita G, Forrester, Terrence, Franco, Oscar H, Gansevoort, Ron T, Gejman, Pablo V, Gieger, Christian, Gottesman, Omri, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Alistair S, Harris, Tamara B, Hattersley, Andrew T, Hicks, Andrew A, Hindorff, Lucia A, Hingorani, Aroon D, Hofman, Albert, Homuth, Georg, Kees Hovingh, G, Humphries, Steve E, Hunt, Steven C, Hyppönen, Elina, Illig, Thomas, Jacobs, Kevin B, Jarvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Johansen, Berit, Jousilahti, Pekka, Wouter Jukema, J, Jula, Antti M, Kaprio, Jaakko, Kastelein, John J P, Keinanen-Kiukaanniemi, Sirkka M, Kiemeney, Lambertus A, Knekt, Paul, Kooner, Jaspal S, Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T, Kumari, Meena, Kuusisto, Johanna, Lakka, Timo A, Langenberg, Claudia, Le Marchand, Loic, Lehtimäki, Terho, Lyssenko, Valeriya, Männistö, Satu, Marette, André, Matise, Tara C, McKenzie, Colin A, McKnight, Barbara, Moll, Frans L, Morris, Andrew D, Morris, Andrew P, Murray, Jeffrey C, Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J, Ong, Ken K, Madden, Pamela A F, Pasterkamp, Gerard, Peden, John F, Peters, Annette, Postma, Dirkje S, Pramstaller, Peter P, Price, Jackie F, Qi, Lu, Raitakari, Olli T, Rankinen, Tuomo, Rao, D C, Rice, Treva K, Ridker, Paul M, Rioux, John D, Ritchie, Marylyn D, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Saramies, Jouko, Sarzynski, Mark A, Schunkert, Heribert, Schwarz, Peter E H, Sever, Peter, Shuldiner, Alan R, Sinisalo, Juha, Stolk, Ronald P, Strauch, Konstantin, Tönjes, Anke, Trégouët, David-Alexandre, Tremblay, Angelo, Tremoli, Elena, Virtamo, Jarmo, Vohl, Marie-Claude, Völker, Uwe, Waeber, Gérard, Willemsen, Gonneke, Witteman, Jacqueline C, Zillikens, M Carola, Adair, Linda S, Amouyel, Philippe, Asselbergs, Folkert W, Assimes, Themistocles L, Bochud, Murielle, Boehm, Bernhard O, Boerwinkle, Eric, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Cauchi, Stéphane, Chambers, John C, Chanock, Stephen J, Cooper, Richard S, de Bakker, Paul I W, Dedoussis, George, Ferrucci, Luigi, Franks, Paul W, Froguel, Philippe, Groop, Leif C, Haiman, Christopher A, Hamsten, Anders, Hui, Jennie, Hunter, David J, Hveem, Kristian, Kaplan, Robert C, Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, Martin, Nicholas G, März, Winfried, Melbye, Mads, Metspalu, Andres, Moebus, Susanne, Munroe, Patricia B, Njølstad, Inger, Oostra, Ben A, Palmer, Colin N A, Pedersen, Nancy L, Perola, Markus, Pérusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E, Saleheen, Danish, Sattar, Naveed, Schadt, Eric E, Schlessinger, David, Eline Slagboom, P, Snieder, Harold, Spector, Tim D, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van der Harst, Pim, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wichmann, H-Erich, Wilson, James F, Zanen, Pieter, Borecki, Ingrid B, Deloukas, Panos, Fox, Caroline S, Heid, Iris M, O'Connell, Jeffrey R, Strachan, David P, Stefansson, Kari, van Duijn, Cornelia M, Abecasis, Gonçalo R, Franke, Lude, Frayling, Timothy M, McCarthy, Mark I, Visscher, Peter M, Scherag, André, Willer, Cristen J, Boehnke, Michael, Mohlke, Karen L, Lindgren, Cecilia M, Beckmann, Jacques S, Barroso, Inês, North, Kari E, Ingelsson, Erik, Hirschhorn, Joel N, Loos, Ruth J F, Speliotes, Elizabeth K, Locke, Adam E, Kahali, Bratati, Berndt, Sonja I, Justice, Anne E, Pers, Tune H, Day, Felix R, Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L, Yang, Jian, Croteau-Chonka, Damien C, Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltán, Luan, Jian'an, Mägi, Reedik, Randall, Joshua C, Winkler, Thomas W, Wood, Andrew R, Workalemahu, Tsegaselassie, Faul, Jessica D, Smith, Jennifer A, Hua Zhao, Jing, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Åsa K, Karjalainen, Juha, Schmidt, Ellen M, Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bolton, Jennifer L, Bragg-Gresham, Jennifer L, Buyske, Steven, Demirkan, Ayse, Deng, Guohong, Ehret, Georg B, Feenstra, Bjarke, Feitosa, Mary F, Fischer, Krista, Goel, Anuj, Gong, Jian, Jackson, Anne U, Kanoni, Stavroula, Kleber, Marcus E, Kristiansson, Kati, Lim, Unhee, Lotay, Vaneet, Mangino, Massimo, Mateo Leach, Irene, Medina-Gomez, Carolina, Medland, Sarah E, Nalls, Michael A, Palmer, Cameron D, Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J, Prokopenko, Inga, Shungin, Dmitry, Stančáková, Alena, Strawbridge, Rona J, Ju Sung, Yun, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W, van Setten, Jessica, Van Vliet-Ostaptchouk, Jana V, Wang, Zhaoming, Yengo, Loïc, Zhang, Weihua, Isaacs, Aaron, Albrecht, Eva, Ärnlöv, Johan, Arscott, Gillian M, Attwood, Antony P, Bandinelli, Stefania, Barrett, Amy, Bas, Isabelita N, Bellis, Claire, Bennett, Amanda J, Berne, Christian, Blagieva, Roza, Blüher, Matthias, Böhringer, Stefan, Bonnycastle, Lori L, Böttcher, Yvonne, Boyd, Heather A, Bruinenberg, Marcel, Caspersen, Ida H, Ida Chen, Yii-Der, Clarke, Robert, Warwick Daw, E, de Craen, Anton J M, Delgado, Graciela, Dimitriou, Maria, Doney, Alex S F, Eklund, Niina, Estrada, Karol, Eury, Elodie, Folkersen, Lasse, Fraser, Ross M, Garcia, Melissa E, Geller, Frank, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S, Golay, Alain, Goodall, Alison H, Gordon, Scott D, Gorski, Mathias, Grabe, Hans-Jörgen, Grallert, Harald, Grammer, Tanja B, Gräßler, Jürgen, Grönberg, Henrik, Groves, Christopher J, Gusto, Gaëlle, Haessler, Jeffrey, Hall, Per, Haller, Toomas, Hallmans, Goran, Hartman, Catharina A, Hassinen, Maija, Hayward, Caroline, Heard-Costa, Nancy L, Helmer, Quinta, Hengstenberg, Christian, Holmen, Oddgeir, Hottenga, Jouke-Jan, James, Alan L, Jeff, Janina M, Johansson, Åsa, Jolley, Jennifer, Juliusdottir, Thorhildur, Kinnunen, Leena, Koenig, Wolfgang, Koskenvuo, Markku, Kratzer, Wolfgang, Laitinen, Jaana, Lamina, Claudia, Leander, Karin, Lee, Nanette R, Lichtner, Peter, Lind, Lars, Lindström, Jaana, Sin Lo, Ken, Lobbens, Stéphane, Lorbeer, Roberto, Lu, Yingchang, Mach, François, Magnusson, Patrik K E, Mahajan, Anubha, McArdle, Wendy L, McLachlan, Stela, Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Moayyeri, Alireza, Monda, Keri L, Morken, Mario A, Mulas, Antonella, Müller, Gabriele, Müller-Nurasyid, Martina, Musk, Arthur W, Nagaraja, Ramaiah, Nöthen, Markus M, Nolte, Ilja M, Pilz, Stefan, Rayner, Nigel W, Renstrom, Frida, Rettig, Rainer, Ried, Janina S, Ripke, Stephan, Robertson, Neil R, Rose, Lynda M, Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Schumacher, Fredrick R, Scott, William R, Seufferlein, Thomas, Shi, Jianxin, Vernon Smith, Albert, Smolonska, Joanna, Stanton, Alice V, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stringham, Heather M, Sundström, Johan, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tan, Sian-Tsung, Tayo, Bamidele O, Thorand, Barbara, Thorleifsson, Gudmar, Tyrer, Jonathan P, Uh, Hae-Won, Vandenput, Liesbeth, Verhulst, Frank C, Vermeulen, Sita H, Verweij, Niek, Vonk, Judith M, Waite, Lindsay L, Warren, Helen R, Waterworth, Dawn, Weedon, Michael N, Wilkens, Lynne R, Willenborg, Christina, Wilsgaard, Tom, Wojczynski, Mary K, Wong, Andrew, Wright, Alan F, Zhang, Qunyuan, Brennan, Eoin P, Choi, Murim, Dastani, Zari, Drong, Alexander W, Eriksson, Per, Franco-Cereceda, Anders, Gådin, Jesper R, Gharavi, Ali G, Goddard, Michael E, Handsaker, Robert E, Huang, Jinyan, Karpe, Fredrik, Kathiresan, Sekar, Keildson, Sarah, Kiryluk, Krzysztof, Kubo, Michiaki, Lee, Jong-Young, Liang, Liming, Lifton, Richard P, Ma, Baoshan, McCarroll, Steven A, McKnight, Amy J, Min, Josine L, Moffatt, Miriam F, Montgomery, Grant W, Murabito, Joanne M, Nicholson, George, Nyholt, Dale R, Okada, Yukinori, Perry, John R B, Dorajoo, Rajkumar, Reinmaa, Eva, Salem, Rany M, Sandholm, Niina, Scott, Robert A, Stolk, Lisette, Takahashi, Atsushi, Tanaka, Toshihiro, Van't Hooft, Ferdinand M, Vinkhuyzen, Anna A E, Westra, Harm-Jan, Zheng, Wei, Zondervan, Krina T, Heath, Andrew C, Arveiler, Dominique, Bakker, Stephan J L, Beilby, John, Bergman, Richard N, Blangero, John, Bovet, Pascal, Campbell, Harry, Caulfield, Mark J, Cesana, Giancarlo, Chakravarti, Aravinda, Chasman, Daniel I, Chines, Peter S, Collins, Francis S, Crawford, Dana C, Adrienne Cupples, L, Cusi, Daniele, Danesh, John, de Faire, Ulf, den Ruijter, Hester M, Dominiczak, Anna F, Erbel, Raimund, Erdmann, Jeanette, Eriksson, Johan G, Farrall, Martin, Felix, Stephan B, Ferrannini, Ele, Ferrières, Jean, Ford, Ian, Forouhi, Nita G, Forrester, Terrence, Franco, Oscar H, Gansevoort, Ron T, Gejman, Pablo V, Gieger, Christian, Gottesman, Omri, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Alistair S, Harris, Tamara B, Hattersley, Andrew T, Hicks, Andrew A, Hindorff, Lucia A, Hingorani, Aroon D, Hofman, Albert, Homuth, Georg, Kees Hovingh, G, Humphries, Steve E, Hunt, Steven C, Hyppönen, Elina, Illig, Thomas, Jacobs, Kevin B, Jarvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Johansen, Berit, Jousilahti, Pekka, Wouter Jukema, J, Jula, Antti M, Kaprio, Jaakko, Kastelein, John J P, Keinanen-Kiukaanniemi, Sirkka M, Kiemeney, Lambertus A, Knekt, Paul, Kooner, Jaspal S, Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T, Kumari, Meena, Kuusisto, Johanna, Lakka, Timo A, Langenberg, Claudia, Le Marchand, Loic, Lehtimäki, Terho, Lyssenko, Valeriya, Männistö, Satu, Marette, André, Matise, Tara C, McKenzie, Colin A, McKnight, Barbara, Moll, Frans L, Morris, Andrew D, Morris, Andrew P, Murray, Jeffrey C, Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J, Ong, Ken K, Madden, Pamela A F, Pasterkamp, Gerard, Peden, John F, Peters, Annette, Postma, Dirkje S, Pramstaller, Peter P, Price, Jackie F, Qi, Lu, Raitakari, Olli T, Rankinen, Tuomo, Rao, D C, Rice, Treva K, Ridker, Paul M, Rioux, John D, Ritchie, Marylyn D, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Saramies, Jouko, Sarzynski, Mark A, Schunkert, Heribert, Schwarz, Peter E H, Sever, Peter, Shuldiner, Alan R, Sinisalo, Juha, Stolk, Ronald P, Strauch, Konstantin, Tönjes, Anke, Trégouët, David-Alexandre, Tremblay, Angelo, Tremoli, Elena, Virtamo, Jarmo, Vohl, Marie-Claude, Völker, Uwe, Waeber, Gérard, Willemsen, Gonneke, Witteman, Jacqueline C, Zillikens, M Carola, Adair, Linda S, Amouyel, Philippe, Asselbergs, Folkert W, Assimes, Themistocles L, Bochud, Murielle, Boehm, Bernhard O, Boerwinkle, Eric, Bornstein, Stefan R, Bottinger, Erwin P, Bouchard, Claude, Cauchi, Stéphane, Chambers, John C, Chanock, Stephen J, Cooper, Richard S, de Bakker, Paul I W, Dedoussis, George, Ferrucci, Luigi, Franks, Paul W, Froguel, Philippe, Groop, Leif C, Haiman, Christopher A, Hamsten, Anders, Hui, Jennie, Hunter, David J, Hveem, Kristian, Kaplan, Robert C, Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, Martin, Nicholas G, März, Winfried, Melbye, Mads, Metspalu, Andres, Moebus, Susanne, Munroe, Patricia B, Njølstad, Inger, Oostra, Ben A, Palmer, Colin N A, Pedersen, Nancy L, Perola, Markus, Pérusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E, Saleheen, Danish, Sattar, Naveed, Schadt, Eric E, Schlessinger, David, Eline Slagboom, P, Snieder, Harold, Spector, Tim D, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van der Harst, Pim, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wichmann, H-Erich, Wilson, James F, Zanen, Pieter, Borecki, Ingrid B, Deloukas, Panos, Fox, Caroline S, Heid, Iris M, O'Connell, Jeffrey R, Strachan, David P, Stefansson, Kari, van Duijn, Cornelia M, Abecasis, Gonçalo R, Franke, Lude, Frayling, Timothy M, McCarthy, Mark I, Visscher, Peter M, Scherag, André, Willer, Cristen J, Boehnke, Michael, Mohlke, Karen L, Lindgren, Cecilia M, Beckmann, Jacques S, Barroso, Inês, North, Kari E, Ingelsson, Erik, Hirschhorn, Joel N, Loos, Ruth J F, and Speliotes, Elizabeth K

Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis., De fem sista författarna delar sistaförfattarskapet.

Published
2015
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29. Familial hypercholesterolaemia: A global call to arms

Author

Vallejo-Vaz, Antonio J., Rao Kondapally Seshasai, Sreenivasa, Cole, Della, Kees Hovingh, G., Kastelein, John J. P., Mata, Pedro, Raal, Frederick J., Santos, Raul D., Soran, Handrean, Watts, Gerald F., Abifadel, Marianne, Aguilar-Salinas, Carlos A., Akram, Asif, Alnouri, Fahad, Alonso, Rodrigo, Al-Rasadi, Khalid, Banach, Maciej, Bogsrud, Martin P., Bourbon, Mafalda, Bruckert, Eric, Car, Josip, Corral, Pablo, Descamps, Olivier, Dieplinger, Hans, Durst, Ronen, Freiberger, Tomas, Gaspar, Isabel M., Genest, Jaques, Harada-Shiba, Mariko, Jiang, Lixin, Kayikcioglu, Meral, Lam, Carolyn S. P., Latkovskis, Gustavs, Laufs, Ulrich, Liberopoulos, Evangelos, Nilsson, Lennart, Nordestgaard, Borge G., ODonoghue, John M., Sahebkar, Amirhossein, Schunkert, Heribert, Shehab, Abdulla, Stoll, Mario, Su, Ta-Chen, Susekov, Andrey, Widen, Elisabeth, Catapano, Alberico L., Ray, Kausik K., Vallejo-Vaz, Antonio J., Rao Kondapally Seshasai, Sreenivasa, Cole, Della, Kees Hovingh, G., Kastelein, John J. P., Mata, Pedro, Raal, Frederick J., Santos, Raul D., Soran, Handrean, Watts, Gerald F., Abifadel, Marianne, Aguilar-Salinas, Carlos A., Akram, Asif, Alnouri, Fahad, Alonso, Rodrigo, Al-Rasadi, Khalid, Banach, Maciej, Bogsrud, Martin P., Bourbon, Mafalda, Bruckert, Eric, Car, Josip, Corral, Pablo, Descamps, Olivier, Dieplinger, Hans, Durst, Ronen, Freiberger, Tomas, Gaspar, Isabel M., Genest, Jaques, Harada-Shiba, Mariko, Jiang, Lixin, Kayikcioglu, Meral, Lam, Carolyn S. P., Latkovskis, Gustavs, Laufs, Ulrich, Liberopoulos, Evangelos, Nilsson, Lennart, Nordestgaard, Borge G., ODonoghue, John M., Sahebkar, Amirhossein, Schunkert, Heribert, Shehab, Abdulla, Stoll, Mario, Su, Ta-Chen, Susekov, Andrey, Widen, Elisabeth, Catapano, Alberico L., and Ray, Kausik K.

Abstract

n/a

Published
2015
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30. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial

Author

Raal, Frederick J., Stein, Evan A., Dufour, Robert, Turner, Traci, Civeira, Fernando, Burgess, Lesley, Langslet, Gisle, Scott, Russell, Olsson, Anders, Sullivan, David, Kees Hovingh, G., Cariou, Bertrand, Gouni-Berthold, Ioanna, Somaratne, Ransi, Bridges, Ian, Scott, Rob, Wasserman, Scott M., Gaudet, Daniel, Raal, Frederick J., Stein, Evan A., Dufour, Robert, Turner, Traci, Civeira, Fernando, Burgess, Lesley, Langslet, Gisle, Scott, Russell, Olsson, Anders, Sullivan, David, Kees Hovingh, G., Cariou, Bertrand, Gouni-Berthold, Ioanna, Somaratne, Ransi, Bridges, Ian, Scott, Rob, Wasserman, Scott M., and Gaudet, Daniel

Abstract

Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19,2013.331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2.6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4.1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. Findings Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=1

Published
2015
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31. A systematic review and meta-analysis of the effect of statins on plasma asymmetric dimethylarginine concentrations

Author

Serban, Corina, primary, Sahebkar, Amirhossein, additional, Ursoniu, Sorin, additional, Mikhailidis, Dimitri P., additional, Rizzo, Manfredi, additional, Lip, Gregory Y.H., additional, Kees Hovingh, G., additional, Kastelein, John J.P., additional, Kalinowski, Leszek, additional, Rysz, Jacek, additional, and Banach, Maciej, additional

Published
2015
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32. Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

Author

Holmes, Michael V., Simon, Tabassome, J Exeter, Holly, Folkersen, Lasse, Asselbergs, Folkert W., Guardiola, Montse, Cooper, Jackie A., Palmen, Jutta, Hubacek, Jaroslav A., Carruthers, Kathryn F., Horne, Benjamin D., Brunisholz, Kimberly D., Mega, Jessica L., Van Iperen, Erik P A, Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J W., Kees Hovingh, G, Dehghan, Abbas, Nelson, Christopher P., Kotti, Salma, Danchin, Nicolas, Scholz, Markus, Haase L., Christiane, Rothenbacher, Dietrich, Swerdlow, Daniel I., Kuchenbaecker, Karoline B., Staines-Urias, Eleonora, Goel, Anuj, van t Hooft, Ferdinand, Gertow, Karl, de Faire, Ulf, Panayiotou, Andrie G., Tremoli, Elena, Baldassarre, Damiano, Veglia, Fabrizio, Holdt, Lesca M., Beutner, Frank, Gansevoort, Ron T., Navis, Gerjan J., Mateo Leach, Irene, Breitling, Lutz P., Brenner, Hermann, Thiery, Joachim, Dallmeier, Dhayana, Franco-Cereceda, Anders, Boer, Jolanda M A., Stephens, Jeffrey W., Hofker, Marten H., Tedgui, Alain, Hofman, Albert, Uitterlinden, Andre G., Adamkova, Vera, Pitha, Jan, Onland-Moret, Charlotte N., Cramer, Maarten J., Nathoe, Hendrik M., Spiering, Wilko, Klungel, Olaf H., Kumari, Meena, Whincup, Peter H., Morrow, David A., Braund, Peter S., Hall, Alistair S., Olsson, Anders G., Doevendans, Pieter A., Trip, Mieke D., Tobin, Martin D., Hamsten, Anders, Watkins, Hugh, Koenig, Wolfgang, Nicolaides, Andrew N., Teupser, Daniel, Day, Ian N M, F Carlquist, John, Gaunt, Tom R., Ford, Ian, Sattar, Naveed, Tsimikas, Sotirios, Schwartz, Gregory G., Lawlor, Debbie A., Morris, Richard W., Sandhu, Manjinder S., Poledne, Rudolf, Maitland-van der Zee, Anke H., Khaw, Kay-Tee, Keating, Brendan J., van der Harst, Pim, Price, Jackie F., Mehta, Shamir R., Yusuf, Salim, Witteman, Jaqueline C M, Franco, Oscar H., Jukema, Wouter J., de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J., Farrall, Martin, Samani, Nilesh J., Kivimaki, Mika, Fox, Keith A A., Humphries, Steve E., Anderson, Jeffrey L., Boekholdt, Matthijs S., Palmer, Tom M., Eriksson, Per, Pare, Guillaume, Hingorani, Aroon D., Sabatine, Marc S., Mallat, Ziad, Casas, Juan P., Talmud, Philippa J., Holmes, Michael V., Simon, Tabassome, J Exeter, Holly, Folkersen, Lasse, Asselbergs, Folkert W., Guardiola, Montse, Cooper, Jackie A., Palmen, Jutta, Hubacek, Jaroslav A., Carruthers, Kathryn F., Horne, Benjamin D., Brunisholz, Kimberly D., Mega, Jessica L., Van Iperen, Erik P A, Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J W., Kees Hovingh, G, Dehghan, Abbas, Nelson, Christopher P., Kotti, Salma, Danchin, Nicolas, Scholz, Markus, Haase L., Christiane, Rothenbacher, Dietrich, Swerdlow, Daniel I., Kuchenbaecker, Karoline B., Staines-Urias, Eleonora, Goel, Anuj, van t Hooft, Ferdinand, Gertow, Karl, de Faire, Ulf, Panayiotou, Andrie G., Tremoli, Elena, Baldassarre, Damiano, Veglia, Fabrizio, Holdt, Lesca M., Beutner, Frank, Gansevoort, Ron T., Navis, Gerjan J., Mateo Leach, Irene, Breitling, Lutz P., Brenner, Hermann, Thiery, Joachim, Dallmeier, Dhayana, Franco-Cereceda, Anders, Boer, Jolanda M A., Stephens, Jeffrey W., Hofker, Marten H., Tedgui, Alain, Hofman, Albert, Uitterlinden, Andre G., Adamkova, Vera, Pitha, Jan, Onland-Moret, Charlotte N., Cramer, Maarten J., Nathoe, Hendrik M., Spiering, Wilko, Klungel, Olaf H., Kumari, Meena, Whincup, Peter H., Morrow, David A., Braund, Peter S., Hall, Alistair S., Olsson, Anders G., Doevendans, Pieter A., Trip, Mieke D., Tobin, Martin D., Hamsten, Anders, Watkins, Hugh, Koenig, Wolfgang, Nicolaides, Andrew N., Teupser, Daniel, Day, Ian N M, F Carlquist, John, Gaunt, Tom R., Ford, Ian, Sattar, Naveed, Tsimikas, Sotirios, Schwartz, Gregory G., Lawlor, Debbie A., Morris, Richard W., Sandhu, Manjinder S., Poledne, Rudolf, Maitland-van der Zee, Anke H., Khaw, Kay-Tee, Keating, Brendan J., van der Harst, Pim, Price, Jackie F., Mehta, Shamir R., Yusuf, Salim, Witteman, Jaqueline C M, Franco, Oscar H., Jukema, Wouter J., de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J., Farrall, Martin, Samani, Nilesh J., Kivimaki, Mika, Fox, Keith A A., Humphries, Steve E., Anderson, Jeffrey L., Boekholdt, Matthijs S., Palmer, Tom M., Eriksson, Per, Pare, Guillaume, Hingorani, Aroon D., Sabatine, Marc S., Mallat, Ziad, Casas, Juan P., and Talmud, Philippa J.

Abstract

Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events., Funding Agencies|BHG programme grant|RG/10/12/28456|UK Medical Research Council (Population Health Scientist Fellowship)|G0802432|British Heart Foundation|RG 10/12/28456RG008/014RG/10/001/27643PG07/133/24260FS 08/ 048/25628|National Institute of Health Research University College London Hospitals Biomedical Research Centre||Dutch Kidney Foundation|E033|Netherlands Organisation for Health Research and Development (NWO VENI)|916.761.70|Dutch Inter University Cardiology Institute Netherlands (ICIN)||Canada Research Chair in Genetic and Molecular Epidemiology||Europe Against Cancer Programme of the European Commission (SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Cancer Society|||EU-LSHM-CT-2006037697

Published
2013
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33. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, Tanya M., primary, Musunuru, Kiran, additional, Smith, Albert V., additional, Edmondson, Andrew C., additional, Stylianou, Ioannis M., additional, Koseki, Masahiro, additional, Pirruccello, James P., additional, Ripatti, Samuli, additional, Chasman, Daniel I., additional, Willer, Cristen J., additional, Johansen, Christopher T., additional, Fouchier, Sigrid W., additional, Isaacs, Aaron, additional, Peloso, Gina M., additional, Barbalic, Maja, additional, Ricketts, Sally L., additional, Bis, Joshua C., additional, Aulchenko, Yurii S., additional, Thorleifsson, Gudmar, additional, Feitosa, Mary F., additional, Chambers, John, additional, Orho-Melander, Marju, additional, Melander, Olle, additional, Johnson, Toby, additional, Li, Xiaohui, additional, Guo, Xiuqing, additional, Li, Mingyao, additional, Shin Cho, Yoon, additional, Jin Go, Min, additional, Jin Kim, Young, additional, Lee, Jong-Young, additional, Park, Taesung, additional, Kim, Kyunga, additional, Sim, Xueling, additional, Twee-Hee Ong, Rick, additional, Croteau-Chonka, Damien C., additional, Lange, Leslie A., additional, Smith, Joshua D., additional, Song, Kijoung, additional, Hua Zhao, Jing, additional, Yuan, Xin, additional, Luan, Jian’an, additional, Lamina, Claudia, additional, Ziegler, Andreas, additional, Zhang, Weihua, additional, Zee, Robert Y. L., additional, Wright, Alan F., additional, Witteman, Jacqueline C. M., additional, Wilson, James F., additional, Willemsen, Gonneke, additional, Wichmann, H.-Erich, additional, Whitfield, John B., additional, Waterworth, Dawn M., additional, Wareham, Nicholas J., additional, Waeber, Gérard, additional, Vollenweider, Peter, additional, Voight, Benjamin F., additional, Vitart, Veronique, additional, Uitterlinden, Andre G., additional, Uda, Manuela, additional, Tuomilehto, Jaakko, additional, Thompson, John R., additional, Tanaka, Toshiko, additional, Surakka, Ida, additional, Stringham, Heather M., additional, Spector, Tim D., additional, Soranzo, Nicole, additional, Smit, Johannes H., additional, Sinisalo, Juha, additional, Silander, Kaisa, additional, Sijbrands, Eric J. G., additional, Scuteri, Angelo, additional, Scott, James, additional, Schlessinger, David, additional, Sanna, Serena, additional, Salomaa, Veikko, additional, Saharinen, Juha, additional, Sabatti, Chiara, additional, Ruokonen, Aimo, additional, Rudan, Igor, additional, Rose, Lynda M., additional, Roberts, Robert, additional, Rieder, Mark, additional, Psaty, Bruce M., additional, Pramstaller, Peter P., additional, Pichler, Irene, additional, Perola, Markus, additional, Penninx, Brenda W. J. H., additional, Pedersen, Nancy L., additional, Pattaro, Cristian, additional, Parker, Alex N., additional, Pare, Guillaume, additional, Oostra, Ben A., additional, O’Donnell, Christopher J., additional, Nieminen, Markku S., additional, Nickerson, Deborah A., additional, Montgomery, Grant W., additional, Meitinger, Thomas, additional, McPherson, Ruth, additional, McCarthy, Mark I., additional, McArdle, Wendy, additional, Masson, David, additional, Martin, Nicholas G., additional, Marroni, Fabio, additional, Mangino, Massimo, additional, Magnusson, Patrik K. E., additional, Lucas, Gavin, additional, Luben, Robert, additional, Loos, Ruth J. F., additional, Lokki, Marja-Liisa, additional, Lettre, Guillaume, additional, Langenberg, Claudia, additional, Launer, Lenore J., additional, Lakatta, Edward G., additional, Laaksonen, Reijo, additional, Kyvik, Kirsten O., additional, Kronenberg, Florian, additional, König, Inke R., additional, Khaw, Kay-Tee, additional, Kaprio, Jaakko, additional, Kaplan, Lee M., additional, Johansson, Åsa, additional, Jarvelin, Marjo-Riitta, additional, Cecile J. W. Janssens, A., additional, Ingelsson, Erik, additional, Igl, Wilmar, additional, Kees Hovingh, G., additional, Hottenga, Jouke-Jan, additional, Hofman, Albert, additional, Hicks, Andrew A., additional, Hengstenberg, Christian, additional, Heid, Iris M., additional, Hayward, Caroline, additional, Havulinna, Aki S., additional, Hastie, Nicholas D., additional, Harris, Tamara B., additional, Haritunians, Talin, additional, Hall, Alistair S., additional, Gyllensten, Ulf, additional, Guiducci, Candace, additional, Groop, Leif C., additional, Gonzalez, Elena, additional, Gieger, Christian, additional, Freimer, Nelson B., additional, Ferrucci, Luigi, additional, Erdmann, Jeanette, additional, Elliott, Paul, additional, Ejebe, Kenechi G., additional, Döring, Angela, additional, Dominiczak, Anna F., additional, Demissie, Serkalem, additional, Deloukas, Panagiotis, additional, de Geus, Eco J. C., additional, de Faire, Ulf, additional, Crawford, Gabriel, additional, Collins, Francis S., additional, Chen, Yii-der I., additional, Caulfield, Mark J., additional, Campbell, Harry, additional, Burtt, Noel P., additional, Bonnycastle, Lori L., additional, Boomsma, Dorret I., additional, Boekholdt, S. Matthijs, additional, Bergman, Richard N., additional, Barroso, Inês, additional, Bandinelli, Stefania, additional, Ballantyne, Christie M., additional, Assimes, Themistocles L., additional, Quertermous, Thomas, additional, Altshuler, David, additional, Seielstad, Mark, additional, Wong, Tien Y., additional, Tai, E-Shyong, additional, Feranil, Alan B., additional, Kuzawa, Christopher W., additional, Adair, Linda S., additional, Taylor Jr, Herman A., additional, Borecki, Ingrid B., additional, Gabriel, Stacey B., additional, Wilson, James G., additional, Holm, Hilma, additional, Thorsteinsdottir, Unnur, additional, Gudnason, Vilmundur, additional, Krauss, Ronald M., additional, Mohlke, Karen L., additional, Ordovas, Jose M., additional, Munroe, Patricia B., additional, Kooner, Jaspal S., additional, Tall, Alan R., additional, Hegele, Robert A., additional, Kastelein, John J.P., additional, Schadt, Eric E., additional, Rotter, Jerome I., additional, Boerwinkle, Eric, additional, Strachan, David P., additional, Mooser, Vincent, additional, Stefansson, Kari, additional, Reilly, Muredach P., additional, Samani, Nilesh J, additional, Schunkert, Heribert, additional, Cupples, L. Adrienne, additional, Sandhu, Manjinder S., additional, Ridker, Paul M, additional, Rader, Daniel J., additional, van Duijn, Cornelia M., additional, Peltonen, Leena, additional, Abecasis, Gonçalo R., additional, Boehnke, Michael, additional, and Kathiresan, Sekar, additional

Published
2010
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34. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.

Author

Wiegman, Albert, Gidding, Samuel S., Watts, Gerald F., John Chapman, M., Ginsberg, Henry N., Cuchel, Marina, Ose, Leiv, Averna, Maurizio, Boileau, Catherine, Borén, Jan, Bruckert, Eric, Catapano, Alberico L., Defesche, Joep C., Descamps, Olivier S., Hegele, Robert A., Kees Hovingh, G., Humphries, Steve E., Kovanen, Petri T., Kuivenhoven, Jan Albert, and Masana, Luis

Abstract

Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FHchildren. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol(LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH. [ABSTRACT FROM AUTHOR]

Published
2015
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35. Homozigot ailevi hiperkolesterolemi: klinisyenlerin tanıyı ve klinik yönetimi geliştirmelerine yönelik yeni anlayışlar ve rehberlik. Avrupa Ateroskleroz Derneği’nin Ailevi Hiperkolesterolemi Üzerine Uzlaşı Paneli yazılı görüşü

Author

Cuchel, Marina, Bruckert, Eric, Ginsberg, Henry N., Raal, Frederick J., Santos, Raul D., Hegele, Robert A., Kuivenhoven, Jan Albert, Nordestgaard, Børge G., Descamps, Olivier S., Steinhagen-Thiessen, Elisabeth, Tybjærg-Hansen, Anne, Watts, Gerald F., Averna, Maurizio, Boileau, Catherine, Borén, Jan, Catapano, Alberico L., Defesche, Joep C., Kees Hovingh, G., Humphries, Steve E., and Kovanen, Petri T.

Abstract

Copyright of Archives of the Turkish Society of Cardiology / Türk Kardiyoloji Derneği Arşivi is the property of KARE Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2015

36. CETP as a Target to Lower CVD Risk: Suspension of Disbelief?

Author

Kees Hovingh, G., Ray, Kausik K., and Matthijs Boekholdt, S.

Subjects
*CHOLESTERYL ester transfer protein, *CARDIOVASCULAR disease prevention, *CARDIOVASCULAR diseases risk factors, *ATHEROSCLEROSIS, *BLOOD proteins
Abstract

The article summarizes data that cast doubt on cholesteryl ester transfer protein (CETP) as therapeutic target to lower cardiovascular disease (CVD). Focus is given on data derived from animal and human studies. Topics discussed include CETP physiology, the role of CETP in atherosclerosis progression in animal models, and population studies of CETP mass and activity.

Published
2015
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37. Response to Barter et al.

Author

Kees Hovingh, G., Ray, Kausik K., and Matthijs Boekholdt, S.

Subjects
*CHOLESTERYL ester transfer protein, *CARDIOVASCULAR disease prevention, *DISEASE risk factors, *PREVENTION
Abstract

The article presents a comment/response to the article by P. J. Barter and colleagues which summarizes data related to cholesteryl ester transfer protein (CETP) as a therapeutic target to lower the risk of cardiovascular disease.

Published
2015

38. Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town

Author

Rosemary J. Jooste, Asier Benito-Vicente, Kévin Chemello, Dee Blackhurst, Zorena Behardien, César Martín, Merel L. Hartgers, G. Kees Hovingh, Joep C. Defesche, Dirk J. Blom, Karen H. Wolmarans, Kepa B. Uribe, Annemiek G. de Jong, Gabriele Solomon, A. David Marais, Gilles Lambert, Brigitte C. Brice, Roeland Huijgen, Regeneron Pharmaceuticals, Fritz Thyssen Foundation, Amsterdam Stollings Foundation, Amsterdam University Funds, Atheros Foundation, Academic Medical Center Foundation, Agence Nationale de la Recherche (France), Eusko Jaurlaritza, Blom, Dirk, Benito-Vicente, Asier, Blackhurst, Dee M., Kees Hovingh, G., Martín, César, Vascular Medicine, Human Genetics, ACS - Atherosclerosis & ischemic syndromes, and Experimental Vascular Medicine

Subjects
0301 basic medicine, Male, Heredity, Time Factors, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, medicine.disease_cause, chemistry.chemical_compound, South Africa, 0302 clinical medicine, Mutation, Hep G2 Cells, Middle Aged, Lipids, Progression-Free Survival, Pedigree, Cholesterol, Phenotype, Cardiovascular Diseases, Kexin, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Hypercholesterolemia, Risk Assessment, Hyperlipoproteinemia Type II, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, In patient, Genetic Predisposition to Disease, Genetic Association Studies, Aged, business.industry, PCSK9, Subtilisin, Proprotein convertase, medicine.disease, 030104 developmental biology, Endocrinology, HEK293 Cells, chemistry, Heart Disease Risk Factors, Gain of function, business, Biomarkers
Abstract

Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P, This work was funded by Regeneron: R727-CL-1555. Grants received from the Fritz Thyssen Foundation, Amsterdam Stollings Foundation, that is, the Jan Wouter ten Cate Prize, Amsterdam University Funds, and the Atheros Foundation to R. Huijgen. Grants received from Academic Medical Center Young Talent Fund, grant received by the Academic Medical Center Foundation, and the Atheros Foundation to M.L. Hartgers. Grants received from Programme de Recherche Hospitalière en Santé ANR-16-RHUS-0007 to K. Chemello and G. Lambert. Grants received from Basque Government (Grupos Consolidados IT1264-19) to A. Benito-Vicente, K.B. Uribe, and C. Martin.

Published
2021

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