PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

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• 作者：Dr Amand F Schmidt ; PhD^a ; ^e ; ^* ; ^{amand.schmidt@ucl.ac.uk} ; Daniel I Swerdlow ; PhD^a ; ^f ; ^* ; Michael V Holmes ; PhD^k ; ^l ; ^* ; Riyaz S Patel ; MD^a ; ^e ; ⁿ ; Zammy Fairhurst-Hunter ; MSc^m ; Donald M Lyall ; PhD^o ; Fernando Pires Hartwig ; MSc^r ; Prof Bernardo Lessa Horta ; PhD^r ; Prof Elina Hyppö ; nen ; PhD^s ; ^u ; ^v ; Prof Christine Power ; PhD^u ; Max Moldovan ; PhD^t ; ^w ; Erik van Iperen ; MSc^x ; ^y ; Prof G Kees Hovingh ; PhD^z ; Ilja Demuth ; PhD^ab ; ^ac ; Kristina Norman ; PhD^ab ; Prof Elisabeth Steinhagen-Thiessen ; MD^ab ; Juri Demuth ; PhD^ad ; Prof Lars Bertram ; MD^g ; ^ae ; Tian Liu ; PhD^af ; ^ag ; Stefan Coassin ; PhD^ah ; Prof Johann Willeit ; PhD^ai ; Stefan Kiechl ; MD^ai ; Karin Willeit ; MD^ai ; Dan Mason ; PhD^aj ; Prof John Wright ; FRCP^aj ; Prof Richard Morris ; PhD^ak ; Prof Goya Wanamethee ; PhD^b ; Prof Peter Whincup ; FRCP^al ; Prof Yoav Ben-Shlomo ; PhD^ak ; Stela McLachlan ; PhD^am ; Prof Jackie F Price ; MD^am ; Prof Mika Kivimaki ; PhD^c ; Catherine Welch ; PhD^c ; Adelaida Sanchez-Galvez ; PhD^c ; Pedro Marques-Vidal ; PhD^ao ; Andrew Nicolaides ; PhD^h ; ^ap ; Andrie G Panayiotou ; PhD^aq ; N Charlotte Onland-Moret ; PhD^ar ; Prof Yvonne T van der Schouw ; PhD^ar ; Giuseppe Matullo ; PhD^at ; ^au ; Giovanni Fiorito ; PhD^at ; ^au ; Simonetta Guarrera ; MSc^at ; ^au ; Carlotta Sacerdote ; PhD^av ; ^aw ; Prof Nicholas J Wareham ; PhD^ax ; Claudia Langenberg ; PhD^ax ; Robert Scott ; PhD^ax ; Jian'an Luan ; PhD^ax ; Prof Martin Bobak ; PhD^c ; Prof Sofia Malyutina ; PhD^ay ; ^az ; Andrzej Pająk ; PhD^ba
• 刊名：The Lancet Diabetes & Endocrinology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：5
• 期：2
• 页码：97-105
• 全文大小：589 K
• 卷排序：5

文摘

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.MethodsIn 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.FindingsData 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).InterpretationPCSK9 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.FundingBritish Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.