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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. and Luan, Jian'an, et al. (2017) In Nature Genetics 49(1). p.17-26
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 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.... (More)

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.

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Nature Genetics
volume
49
issue
1
pages
10 pages
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Nature Publishing Group
external identifiers
  • scopus:84995459787
  • wos:000390976600007
ISSN
1061-4036
DOI
10.1038/ng.3714
language
English
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yes
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ad635737-7a42-44fa-9cfd-ae3b61ad8d3e
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2017-03-24 11:59:13
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2017-09-18 11:34:08
@article{ad635737-7a42-44fa-9cfd-ae3b61ad8d3e,
  abstract     = {<p>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.</p>},
  author       = {Lotta, Luca A. and Gulati, Pawan and Day, Felix R and Payne, Felicity and Ongen, Halit and van de Bunt, Martijn and Gaulton, Kyle J and Eicher, John D. and Sharp, Stephen J. and Luan, Jian'an and De Lucia Rolfe, Emanuella and Stewart, Isobel D. and Wheeler, Eleanor and Willems, Sara M and Adams, Claire and Yaghootkar, Hanieh and Sharp, Stephen J. and Forouhi, Nita G. and Kerrison, Nicola D. and Sims, Matt and Lucarelli, Debora M E and Deloukas, Panos and McCarthy, Mark I. and Arriola, Larraitz and Balkau, Beverley and Barricarte, Aurelio and Boeing, Heiner and Franks, Paul W. and Gonzalez, Carlos and Grioni, Sara and Kaaks, Rudolf and Key, Timothy J and Navarro, Carmen and Nilsson, Peter M. and Overvad, Kim and Palli, Domenico and Panico, Salvatore and Quirós, J Ramón and Rolandsson, Olov and Sacerdote, Carlotta and Salamanca-Fernández, Elena and Slimani, Nadia and Tjonneland, Anne and Tumino, Rosario and Spijkerman, Annemieke M. W. and van der A, Daphne L. and van der Schouw, Yvonne T. and Riboli, Elio and Semple, Robert K and Stears, Anna and George, Stella and Walker, Mark and Gurnell, Ellie and Maguire, Deirdre and Mukhtar, Rasha and Nag, Sath and Adler, Amanda and Soeters, Maarten R. and Laji, Ken and Watt, Alistair and Aylwin, Simon and Johnson, Andrew and Rayman, Gerry and Hanna, Fahmy and Ellard, Sian and Ross, Richard J and Blaslov, Kristina and Duvnjak, Lea Smirčić and Khaw, Kay Tee and Johnson, Andrew D. and Frayling, Timothy and Perry, John R. B. and Dermitzakis, Emmanouil T. and Barroso, Inês and Wareham, Nicholas J and Savage, David B and Langenberg, Claudia and O'Rahilly, Stephen and Scott, Robert A. and ,  and , },
  issn         = {1061-4036},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {17--26},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance},
  url          = {http://dx.doi.org/10.1038/ng.3714},
  volume       = {49},
  year         = {2017},
}