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dc.contributor.authorLotta, LA
dc.contributor.authorGulati, P
dc.contributor.authorDay, FR
dc.contributor.authorPayne, F
dc.contributor.authorOngen, H
dc.contributor.authorvan de Bunt, M
dc.contributor.authorGaulton, KJ
dc.contributor.authorEicher, JD
dc.contributor.authorSharp, SJ
dc.contributor.authorLuan, J
dc.contributor.authorDe Lucia Rolfe, E
dc.contributor.authorStewart, ID
dc.contributor.authorWheeler, E
dc.contributor.authorWillems, SM
dc.contributor.authorAdams, C
dc.contributor.authorYaghootkar, H
dc.contributor.authorEPIC-InterAct Consortium
dc.contributor.authorCambridge FPLD1 Consortium
dc.contributor.authorForouhi, NG
dc.contributor.authorKhaw, K-T
dc.contributor.authorJohnson, AD
dc.contributor.authorSemple, RK
dc.contributor.authorFrayling, T
dc.contributor.authorPerry, JRB
dc.contributor.authorDermitzakis, E
dc.contributor.authorMcCarthy, MI
dc.contributor.authorBarroso, I
dc.contributor.authorWareham, NJ
dc.contributor.authorSavage, DB
dc.contributor.authorLangenberg, C
dc.contributor.authorO'Rahilly, S
dc.contributor.authorScott, RA
dc.date.accessioned2017-03-07T14:40:59Z
dc.date.issued2016-11-14
dc.description.abstractInsulin 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.en_GB
dc.description.sponsorshipWe are grateful for the OP9-K cells kindly shared by the laboratory of A. Kopin (Tufts Medical Center). The authors gratefully acknowledge the help of the MRC Epidemiology Unit Support Teams, including the Field Teams, the Laboratory Team and the Data Management Team, and of the staff of the Wellcome Trust Clinical Research Facility. 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).en_GB
dc.identifier.citationVol. 49, pp. 17 - 26en_GB
dc.identifier.doi10.1038/ng.3714
dc.identifier.otherng.3714
dc.identifier.urihttp://hdl.handle.net/10871/26303
dc.language.isoenen_GB
dc.publisherNature Publishing Groupen_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/27841877en_GB
dc.rights.embargoreasonPublisher's policy.en_GB
dc.rights© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.en_GB
dc.titleIntegrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.en_GB
dc.typeArticleen_GB
dc.identifier.issn1061-4036
exeter.place-of-publicationUnited Statesen_GB
dc.descriptionPublisheden_GB
dc.descriptionJournal Articleen_GB
dc.descriptionThis is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record.en_GB
dc.identifier.eissn1546-1718
dc.identifier.journalNature Geneticsen_GB


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