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

Author:
  • Luca A. Lotta
  • Pawan Gulati
  • Felix R Day
  • Felicity Payne
  • Halit Ongen
  • Martijn van de Bunt
  • Kyle J Gaulton
  • John D. Eicher
  • Stephen J. Sharp
  • Jian'an Luan
  • Emanuella De Lucia Rolfe
  • Isobel D. Stewart
  • Eleanor Wheeler
  • Sara M Willems
  • Claire Adams
  • Hanieh Yaghootkar
  • Stephen J. Sharp
  • Nita G. Forouhi
  • Nicola D. Kerrison
  • Matt Sims
  • Debora M E Lucarelli
  • Panos Deloukas
  • Mark I. McCarthy
  • Larraitz Arriola
  • Beverley Balkau
  • Aurelio Barricarte
  • Heiner Boeing
  • Paul W. Franks
  • Carlos Gonzalez
  • Sara Grioni
  • Rudolf Kaaks
  • Timothy J Key
  • Carmen Navarro
  • Peter M. Nilsson
  • Kim Overvad
  • Domenico Palli
  • Salvatore Panico
  • J Ramón Quirós
  • Olov Rolandsson
  • Carlotta Sacerdote
  • Elena Salamanca-Fernández
  • Nadia Slimani
  • Anne Tjonneland
  • Rosario Tumino
  • Annemieke M. W. Spijkerman
  • Daphne L. van der A
  • Yvonne T. van der Schouw
  • Elio Riboli
  • Robert K Semple
  • Anna Stears
  • Stella George
  • Mark Walker
  • Ellie Gurnell
  • Deirdre Maguire
  • Rasha Mukhtar
  • Sath Nag
  • Amanda Adler
  • Maarten R. Soeters
  • Ken Laji
  • Alistair Watt
  • Simon Aylwin
  • Andrew Johnson
  • Gerry Rayman
  • Fahmy Hanna
  • Sian Ellard
  • Richard J Ross
  • Kristina Blaslov
  • Lea Smirčić Duvnjak
  • Kay Tee Khaw
  • Andrew D. Johnson
  • Timothy Frayling
  • John R. B. Perry
  • Emmanouil T. Dermitzakis
  • Inês Barroso
  • Nicholas J Wareham
  • David B Savage
  • Claudia Langenberg
  • Stephen O'Rahilly
  • Robert A. Scott
Publishing year: 2017-01-01
Language: English
Pages: 17-26
Publication/Series: Nature Genetics
Volume: 49
Issue: 1
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

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.

Keywords

  • Endocrinology and Diabetes
  • Medical Genetics

Other

Published
  • Genetic and Molecular Epidemiology
  • ISSN: 1061-4036
Paul Franks
E-mail: paul [dot] franks [at] med [dot] lu [dot] se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49

60-12-021

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00