1. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
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Schmidt, A.F., Swerdlow, D.I., Holmes, M.V., Patel, R.S., Fairhurst-Hunter, Z., Lyall, D.M., Hartwig, F.P., Horta, B.L., Hypponen, E., Power, C., Moldovan, M., Iperen, E. van, Hovingh, G.K., Demuth, I., Norman, K., Steinhagen-Thiessen, E., Demuth, J., Bertram, L., Liu, T., Coassin, S., Willeit, J., Kiechl, S., Willeit, K., Mason, D., Wright, J., Morris, R., Wanamethee, G., Whincup, P., Ben-Shlomo, Y., McLachlan, S., Price, J.F., Kivimaki, M., Welch, C., Sanchez-Galvez, A., Marques-Vidal, P., Nicolaides, A., Panayiotou, A.G., Onland-Moret, N.C., Schouw, Y.T. van der, Matullo, G., Fiorito, G., Guarrera, S., Sacerdote, C., Wareham, N.J., Langenberg, C., Scott, R., Luan, J.A., Bobak, M., Malyutina, S.A., Pajak, A., Kubinova, R., Tamosiunas, A., Pikhart, H., Husemoen, L.L.N., Grarup, N., Pedersen, O., Hansen, T., Linneberg, A., Simonsen, K.S., Cooper, J., Humphries, S.E., Brilliant, M., Kitchner, T., Hakonarson, H., Carrell, D.S., McCarty, C.A., Kirchner, H.L., Larson, E.B., Crosslin, D.R., Andrade, M. de, Roden, D.M., Denny, J.C., Carty, C., Hancock, S., Attia, J., Holliday, E., Donnell, M.O., Yusuf, S., Chong, M., Pare, G., Harst, P. van der, Said, M.A., Eppinga, R.N., Verweij, N., Snieder, H., Christen, T., Mook-Kanamori, D.O., Gustafsson, S., Lind, L., Ingelsson, E., Pazoki, R., Franco, O., Hofman, A., Uitterlinden, A., Dehghan, A., Teumer, A., Baumeister, S., Dorr, M., Lerch, M.M., Volker, U., Volzke, H., Ward, J., Pell, J.P., Smith, D.J., Meade, T., Maitland-van der Zee, A.H., Baranova, E.V., Young, R., Ford, I., Campbell, A., Padmanabhan, S., Bots, M.L., Grobbee, D.E., Froguel, P., Thuillier, D., Balkau, B., Bonnefond, A., Cariou, B., Smart, M., Bao, Y., Kumari, M., Mahajan, A., Ridker, P.M., Chasman, D.I., Reiner, A.P., Lange, L.A., Ritchie, M.D., Asselbergs, F.W., Casas, J.P., Keating, B.J., Preiss, D., Hingorani, A.D., Sattar, N., LifeLines Cohort Study Grp, UCLEB Consortium, Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dept. of Gastroenterology, Hepatology and Endocrinology, Neuroepidemiology of Ageing Research Unit, Imperial College London, Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Division of Community Health Sciences, St George's University of London, Department of Social Medicine, University of Bristol [Bristol], Finnish Institute of Occupational Health of Helsinki, Department of Epidemiology and Public Health, Institute of Social and Preventive Medicine, Lausanne university hospital, Computer Science Department, University of Cyprus, Cyprus Institute of Neurology and Genetics, University Medical Center [Utrecht], Department of Genetics, Biology and Biochemistry, University of Turin, Institute for Scientific Interchange Foundation, Center for Cancer Prevention, CPO-Piemonte, Unità di epidemiologia dei tumori, Università degli studi di Torino (UNITO)-HuGeF Foundation, Medical Research Council Epidemiology Unit, University of Cambridge [UK] (CAM), Serono Genetics Institute S.A.[Evry], Serono Genetics Institute, Institute of Internal and Preventive Medicine Sibe rian Branch, Russian Academy of Medical Sciences, Institute of Internal Medicine, Novosibirsk State Medical University, Centre for Environmental Health, National Institute of Public Health [Prague], Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), University of Copenhagen = Københavns Universitet (KU), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, Rigshospitalet [Copenhagen], Copenhagen University Hospital, BHF Laboratories, Rayne building, Department of Medicine, 5 University Street, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Population Health Research Institute, Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen [Groningen], Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Limnology, Ecology, Uppsala Universitet [Uppsala], Metacohorts Consortium, Erasmus University Medical Center [Rotterdam] (Erasmus MC), King‘s College London, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Institute for Community Medicine, Department of Oncology and Metabolism [Sheffield, UK], The University of Sheffield [Sheffield, U.K.], European Associated Laboratory [Sheffield, UK] (Sarcoma Research Unit), Robertson Centre for Biostatistics, University of Glasgow, Faculty of Medicine, University of Glasgow, Julius Center for Health Sciences and Primary Care, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), INSERM UMRS 1178, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Department of Pathological Biochemistry, Royal Infirmary, Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], and Apollo - University of Cambridge Repository
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Blood Glucose ,Cohort Studies ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,[SDV]Life Sciences [q-bio] ,Genetic Variation ,Humans ,Genetic Predisposition to Disease ,Cholesterol, LDL ,Mendelian Randomization Analysis ,Proprotein Convertase 9 ,Randomized Controlled Trials as Topic - Abstract
BACKGROUND:Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.METHODS:In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FINDINGS:Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).INTERPRETATION:PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FUNDING:British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
- Published
- 2016
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