Schmidt, Amand F. and Swerdlow, Daniel I. and Holmes, Michael V. and Patel, Riyaz S. and Fairhurst-Hunter, Zammy and Lyall, Donald M. and Hartwig, Fernando Pires and Horta, Bernardo Lessa and Hypponen, Elina and Power, Christine and Moldovan, Max and van Iperen, Erik and Hovingh, G. Kees and Demuth, Ilja and Norman, Kristina and Steinhagen-Thiessen, Elisabeth and Demuth, Juri and Bertram, Lars and Liu, Tian and Coassin, Stefan and Willeit, Johann and Kiechl, Stefan and Willeit, Karin and Mason, Dan and Wright, John and Morris, Richard and Wanamethee, Goya and Whincup, Peter and Ben-Shlomo, Yoav and McLachlan, Stela and Price, Jackie F. and Kivimaki, Mika and Welch, Catherine and Sanchez-Galvez, Adelaida and Marques-Vidal, Pedro and Nicolaides, Andrew and Panayiotou, Andrie G. and Onland-Moret, N. Charlotte and van der Schouw, Yvonne T. and Matullo, Giuseppe and Fiorito, Giovanni and Guarrera, Simonetta and Sacerdote, Carlotta and Wareham, Nicholas J. and Langenberg, Claudia and Scott, Robert and Luan, Jian'an and Bobak, Martin and Malyutina, Sofi A. and Pajak, Andrzej and Kubinova, Ruzena and Tamosiunas, Abdonas and Pikhart, Hynek and Husemoen, Lise Lotte Nystrup and Grarup, Niels and Pedersen, Oluf and Hansen, Torben and Linneberg, Allan and Simonsen, Kenneth Starup and Cooper, Jackie and Humphries, Steve E. and Brilliant, Murray and Kitchner, Terrie and Hakonarson, Hakon and Carrell, David S. and McCarty, Catherine A. and Kirchner, H. Lester and Larson, Eric B. and Crosslin, David R. and de Andrade, Mariza and Roden, Dan M. and Denny, Joshua C. and Carty, Cara and Hancock, Stephen and Attia, John and Holliday, Elizabeth and Donnell, Martin O' and Yusuf, Salim and Chong, Michael and Pare, Guillaume and van der Harst, Pim and Said, M. Abdullah and Eppinga, Ruben N. and Verweij, Niek and Snieder, Harold and Christen, Tim and Mook-Kanamori, Dennis O. and Gustafsson, Stefan and Lind, Lars and Ingelsson, Erik and Pazoki, Raha and Franco, Oscar and Hofman, Albert and Uitterlinden, Andre and Dehghan, Abbas and Teumer, Alexander and Baumeister, Sebastian and Doerr, Marcus and Lerch, Markus M. and Voelker, Uwe and Voelzke, Henry and Ward, Joey and Pell, Jill P. and Smith, Daniel J. and Meade, Tom and Maitland-van der Zee, Anke H. and Baranova, Ekaterina V. and Young, Robin and Ford, Ian and Campbell, Archie and Padmanabhan, Sandosh and Bots, Michiel L. and Grobbee, Diederick E. and Froguel, Philippe and Thuillier, Dorothee and Balkau, Beverley and Bonnefond, Amelie and Cariou, Bertrand and Smart, Melissa and Bao, Yanchun and Kumari, Meena and Mahajan, Anubha and Ridker, Paul M. and Chasman, Daniel I. and Reiner, Alex P. and Lange, Leslie A. and Ritchie, Marylyn D. and Asselbergs, Folkert W. and Casas, Juan-Pablo and Keating, Brendan J. and Preiss, David and Hingorani, Aroon D. and Sattar, Naveed (2017) PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. LANCET DIABETES & ENDOCRINOLOGY, 5 (2). pp. 97-105. ISSN 2213-8587,
Full text not available from this repository. (Request a copy)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 off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects 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 benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | STATIN THERAPY; HEART-DISEASE; ASSOCIATION; HYPERCHOLESTEROLEMIA; METAANALYSIS; CHOLESTEROL; COMMON; ARCHITECTURE; PATHWAYS; INSIGHTS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Epidemiologie und Präventivmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 19 Feb 2019 10:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/492 |
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