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

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_7B4EC296F3C7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.
Périodique
The lancet. Diabetes & endocrinology
Auteur(s)
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., Bobak M., Malyutina S., Pająk A., Kubinova R., Tamosiunas A., Pikhart H., Husemoen L.L., 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., 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.W., Casas J.P., Keating B.J., Preiss D., Hingorani A.D., Sattar N.
Collaborateur(s)
LifeLines Cohort study group, UCLEB consortium
ISSN
2213-8595 (Electronic)
ISSN-L
2213-8587
Statut éditorial
Publié
Date de publication
02/2017
Peer-reviewed
Oui
Volume
5
Numéro
2
Pages
97-105
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.
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 <sub>1c</sub> , 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.
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 <sub>1c</sub> (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m <sup>2</sup> , -0·09 to 0·30).
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.
British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
Mots-clé
Blood Glucose/metabolism, Case-Control Studies, Cholesterol, LDL/blood, Cholesterol, LDL/genetics, Cohort Studies, Diabetes Mellitus, Type 2/blood, Diabetes Mellitus, Type 2/diagnosis, Diabetes Mellitus, Type 2/genetics, Genetic Predisposition to Disease/genetics, Genetic Variation/genetics, Humans, Mendelian Randomization Analysis/methods, Proprotein Convertase 9/genetics, Randomized Controlled Trials as Topic/methods
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/12/2016 17:43
Dernière modification de la notice
20/08/2019 15:37
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