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© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
Author(s): Lotta LA, Gulati P, Day FR, Payne F, Ongen H, Van De Bunt M, Gaulton KJ, Eicher JD, Sharp SJ, Luan J, De Lucia Rolfe E, Stewart ID, Wheeler E, Willems SM, Adams C, Yaghootkar H, Sharp SJ, Forouhi NG, Kerrison ND, Sims M, Lucarelli DME, Deloukas P, McCarthy MI, Arriola L, Balkau B, Barricarte A, Boeing H, Franks PW, Gonzalez C, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Rolandsson O, Sacerdote C, Salamanca-Fernandez E, Slimani N, Tjonneland A, Tumino R, Spijkerman AMW, Van Der A DL, Van Der Schouw YT, Riboli E, Semple RK, Stears A, George S, Walker M, Gurnell E, Maguire D, Mukhtar R, Nag S, Adler A, Soeters MR, Laji K, Watt A, Aylwin S, Johnson A, Rayman G, Hanna F, Ellard S, Ross R, Blaslov K, Duvnjak LS, Khaw K-T, Johnson AD, Frayling T, Perry JRB, Dermitzakis E, Barroso I, Wareham NJ, Savage DB, Langenberg C, O'Rahilly S, Scott RA
Publication type: Article
Publication status: Published
Journal: Nature Genetics
Year: 2017
Volume: 49
Issue: 1
Pages: 17-26
Print publication date: 01/01/2017
Online publication date: 14/11/2016
Acceptance date: 10/10/2016
ISSN (print): 1061-4036
ISSN (electronic): 1546-1718
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/ng.3714
DOI: 10.1038/ng.3714
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