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

Schmidt, AF and Swerdlow, DI and Holmes, MV and Patel, RS and Fairhurst-Hunter, Z and Lyall, DM and Hartwig, FP and Horta, BL and Hyppönen, E and Power, C and Moldovan, M and van Iperen, E and Hovingh, GK and Demuth, I and Norman, K and Steinhagen-Thiessen, E and Demuth, J and Bertram, L and Liu, T and Coassin, S and Willeit, J and Kiechl, S and Willeit, K and Mason, D and Wright, J and Morris, R and Wanamethee, G and Whincup, P and Ben-Shlomo, Y and McLachlan, S and Price, JF and Kivimaki, M and Welch, C and Sanchez-Galvez, A and Marques-Vidal, P and Nicolaides, A and Panayiotou, AG and Onland-Moret, NC and van der Schouw, YT and Matullo, G and Fiorito, G and Guarrera, S and Sacerdote, C and Wareham, NJ and Langenberg, C and Scott, R and Luan, J and Bobak, M and Malyutina, S and Pająk, A and Kubinova, R and Tamosiunas, A and Pikhart, H and Husemoen, LLN and Grarup, N and Pedersen, O and Hansen, T and Linneberg, A and Simonsen, KS and Cooper, J and Humphries, SE and Brilliant, M and Kitchner, T and Hakonarson, H and Carrell, DS and McCarty, CA and Kirchner, HL and Larson, EB and Crosslin, DR and de Andrade, M and Roden, DM and Denny, JC and Carty, C and Hancock, S and Attia, J and Holliday, E and O'Donnell, M and Yusuf, S and Chong, M and Pare, G (2017) 'PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.' The Lancet Diabetes and Endocrinology, 5 (2). 97 - 105. ISSN 2213-8587

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Abstract

© 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license 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, HbA 1c , 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 HbA 1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m 2 , −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.

Item Type: Article
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences > Institute for Social and Economic Research
Depositing User: Jim Jamieson
Date Deposited: 02 Dec 2016 15:26
Last Modified: 17 Aug 2017 17:21
URI: http://repository.essex.ac.uk/id/eprint/18320

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