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Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

Nature Genetics, ISSN: 1546-1718, Vol: 49, Issue: 1, Page: 17-26
2017
  • 449
    Citations
  • 0
    Usage
  • 473
    Captures
  • 9
    Mentions
  • 22
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    449
  • Captures
    473
  • Mentions
    9
    • News Mentions
      7
      • News
        7
    • Blog Mentions
      2
      • Blog
        2
  • Social Media
    22
    • Shares, Likes & Comments
      22
      • Facebook
        22

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Article Description

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.

Bibliographic Details

Luca A. Lotta; Felix R. Day; Stephen J. Sharp; Jian'an Luan; Emanuella De Lucia Rolfe; Isobel D. Stewart; Sara M. Willems; Nita G. Forouhi; Nicola D. Kerrison; Matt Sims; Debora M.E. Lucarelli; John R.B. Perry; Nicholas J. Wareham; Claudia Langenberg; Robert A. Scott; Pawan Gulati; Claire Adams; Panos Deloukas; Robert K. Semple; Inês Barroso; David B. Savage; Stephen O'Rahilly; Felicity Payne; Eleanor Wheeler; Halit Ongen; Emmanouil Dermitzakis; Martijn Van De Bunt; Mark I. McCarthy; Kyle J. Gaulton; John D. Eicher; Andrew D. Johnson; Hanieh Yaghootkar; Timothy Frayling; Kay Tee Khaw; Larraitz Arriola; Aurelio Barricarte; Carmen Navarro; Elena Salamanca-Fernández; Beverley Balkau; Heiner Boeing; Paul W. Franks; Olov Rolandsson; Carlos Gonzalez; Sara Grioni; Rudolf Kaaks; Timothy J. Key; Peter M. Nilsson; Kim Overvad; Domenico Palli; Salvatore Panico; J. Ramón Quirós; Carlotta Sacerdote; Nadia Slimani; Anne Tjonneland; Rosario Tumino; Annemieke M.W. Spijkerman; Daphne L. Van Der A; Yvonne T. Van Der Schouw; Elio Riboli; Anna Stears; Ellie Gurnell; Amanda Adler; Stella George; Mark Walker; Deirdre Maguire; Rasha Mukhtar; Sath Nag; Maarten R. Soeters; Ken Laji; Alistair Watt; Simon Aylwin; Andrew Johnson; Gerry Rayman; Fahmy Hanna; Sian Ellard; Richard Ross; Kristina Blaslov; Lea Smirčić Duvnjak

Springer Science and Business Media LLC

Biochemistry, Genetics and Molecular Biology

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