Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance
Lotta, Luca A.; Gulati, Pawan; Day, Felix R.; Payne, Felicity; Ongen, Halit; Van De Bunt, Martijn; Gaulton, Kyle J.; Eicher, John D.; Sharp, Stephen J.; Luan, Jian'an; De Lucia Rolfe, Emanuella; Stewart, Isobel D.; Wheeler, Eleanor; Willems, Sara M.; Adams, Claire; Yaghootkar, Hanieh; Sharp, Stephen J.; Forouhi, Nita G.; Kerrison, Nicola D.; Sims, Matt; Lucarelli, Debora M E; Deloukas, Panos; McCarthy, Mark I.; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Boeing, Heiner; Franks, Paul W.; Gonzalez, Carlos; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J.; Navarro, Carmen; Nilsson, Peter M.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca-Fernández, Elena; Slimani, Nadia; Tjonneland, Anne; Tumino, Rosario; Spijkerman, Annemieke M W; Van Der A, Daphne L.; Van Der Schouw, Yvonne T.; Riboli, Elio; Semple, Robert K.; Stears, Anna; George, Stella; Walker, Mark; Gurnell, Ellie; Maguire, Deirdre; Mukhtar, Rasha; Nag, Sath; Adler, Amanda; Soeters, Maarten R.; Laji, Ken; Watt, Alistair; Aylwin, Simon; Johnson, Andrew; Rayman, Gerry; Hanna, Fahmy; Ellard, Sian; Ross, Richard; Blaslov, Kristina; Duvnjak, Lea Smirčić; Khaw, Kay Tee; Johnson, Andrew D.; Frayling, Timothy; Perry, John R B; Dermitzakis, Emmanouil; Barroso, Inês; Wareham, Nicholas J.; Savage, David B.; Langenberg, Claudia; O'Rahilly, Stephen; Scott, Robert A.
(2017) Nature Genetics, volume 49, issue 1, pp. 17 - 26
(Article)
Abstract
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
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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.
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Keywords: Genetics, Journal Article, Comparative Study
ISSN: 1061-4036
Publisher: Nature Publishing Group
Note: Funding Information: This study was funded by the UK Medical Research Council through grants MC-UU-12015/1, MC-PC-13046, MC-PC-13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC-UU-12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). Funding for the InterAct project was provided by the EU FP6 program (grant LSHM-CT-2006-037197). This work was funded, in part, through an EFSD Rising Star award to R.A.S. supported by Novo Nordisk. D.B.S. is supported by Wellcome Trust grant 107064. M.I.M. is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. M.v.d.B. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. I.B. is supported by Wellcome Trust grant WT098051. S.O'R. acknowledges funding from the Wellcome Trust (Wellcome Trust Senior Investigator Award 095515/Z/11/Z and Wellcome Trust Strategic Award 100574/Z/12/Z). Publisher Copyright: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
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