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

Schmidt, A. F. et al. (2017) PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes and Endocrinology, 5(2), pp. 97-105. (doi:10.1016/S2213-8587(16)30396-5) (PMID:27908689) (PMCID:PMC5266795)

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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.

Item Type:Articles
Additional Information:This work was supported by a British Heart Foundation Programme Grant (RG/10/12/28456). AFS is funded by University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre (BRC10200) and by a UCL springboard population science fellowship. FWA is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Preiss, Dr David and Ward, Mr Joey and Padmanabhan, Professor Sandosh and Smith, Professor Daniel and Young, Dr Robin and Pell, Professor Jill and Sattar, Professor Naveed and Ford, Professor Ian and Lyall, Dr Donald
Authors: Schmidt, A. F., Swerdlow, D. I., Holmes, M. V., Patel, R. S., Fairhurst-Hunter, Z., Lyall, D. M., Hartwig, F. P., Horta, B. L., Hyppönen, E., Power, C., Moldovan, M., van Iperen, E., 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., van der Schouw, Y. T., Matullo, G., Fiorito, G., Guarrera, S., Sacerdote, C., Wareham, N. J., Langenberg, C., Scott, R., Luan, J.'a., Bobak, M., Malyutina, S., Pająk, A., Kubinova, R., Tamosiunas, A., Pikhart, H., Husemoen, L. L. N., Garup, 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., de Andrade, M., Roden, D. M., Denny, J. C., Carty, C., Hancock, S., Attia, J., Holliday, E., O'Donnell, M., Yusuf, S., Chong, M., Pare, G., van der Harst, P., 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., Dörr, M., Lerch, M. M., Völker, U., Völzke, 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., Casas, J.-P., Keating, B. J., Preiss, D., Hingorani, A. D., and Sattar, N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Lancet Diabetes and Endocrinology
Publisher:Elsevier
ISSN:2213-8587
ISSN (Online):2213-8595
Published Online:29 November 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Lancet Diabetes and Endocrinology 5(2):97-105
Publisher Policy:Reproduced under a Creative Commons License

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