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

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; Cambridge FPLD1 Consortium; EPIC-InterAct Consortium

doi:10.1038/ng.3714

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

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 SimsDebora 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, Cambridge FPLD1 Consortium, EPIC-InterAct Consortium

Research output: Contribution to journal › Article › peer-review

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. 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.

Original language	English
Pages (from-to)	17-26
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3714
Publication status	Published - 2017 Jan 1

Subject classification (UKÄ)

Endocrinology and Diabetes
Medical Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3714

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Lotta, L. A., Gulati, P., Day, F. R., Payne, F., Ongen, H., van de Bunt, M., Gaulton, K. J., Eicher, J. D., Sharp, S. J., Luan, J., De Lucia Rolfe, E., Stewart, I. D., Wheeler, E., Willems, S. M., Adams, C., Yaghootkar, H., Sharp, S. J., Forouhi, N. G., Kerrison, N. D., ... EPIC-InterAct Consortium (2017). Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nature Genetics, 49(1), 17-26. https://doi.org/10.1038/ng.3714

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

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. 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.",

author = "Lotta, {Luca A.} and Pawan Gulati and Day, {Felix R} and Felicity Payne and Halit Ongen and {van de Bunt}, Martijn and Gaulton, {Kyle J} and Eicher, {John D.} and Sharp, {Stephen J.} and Jian'an Luan and {De Lucia Rolfe}, Emanuella and Stewart, {Isobel D.} and Eleanor Wheeler and Willems, {Sara M} and Claire Adams and Hanieh Yaghootkar and Sharp, {Stephen J.} and Forouhi, {Nita G.} and Kerrison, {Nicola D.} and Matt Sims and Lucarelli, {Debora M E} and Panos Deloukas and McCarthy, {Mark I.} and Larraitz Arriola and Beverley Balkau and Aurelio Barricarte and Heiner Boeing and Franks, {Paul W.} and Carlos Gonzalez and Sara Grioni and Rudolf Kaaks and Key, {Timothy J} and Carmen Navarro and Nilsson, {Peter M.} and Kim Overvad and Domenico Palli and Salvatore Panico and Quir{\'o}s, {J Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and Elena Salamanca-Fern{\'a}ndez and Nadia Slimani and Anne Tjonneland and Rosario Tumino and Spijkerman, {Annemieke M. W.} and {van der A}, {Daphne L.} and {van der Schouw}, {Yvonne T.} and Elio Riboli and Semple, {Robert K} and Anna Stears and {Cambridge FPLD1 Consortium} and {EPIC-InterAct Consortium}",

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doi = "10.1038/ng.3714",

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Lotta, LA, Gulati, P, Day, FR, Payne, F, Ongen, H, van de Bunt, M, Gaulton, KJ, Eicher, JD, Sharp, SJ, Luan, J, De Lucia Rolfe, E, Stewart, ID, Wheeler, E, Willems, SM, Adams, C, Yaghootkar, H, Sharp, SJ, Forouhi, NG, Kerrison, ND, Sims, M, Lucarelli, DME, Deloukas, P, McCarthy, MI, Arriola, L, Balkau, B, Barricarte, A, Boeing, H, Franks, PW, Gonzalez, C, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quirós, JR, Rolandsson, O, Sacerdote, C, Salamanca-Fernández, E, Slimani, N, Tjonneland, A, Tumino, R, Spijkerman, AMW, van der A, DL, van der Schouw, YT, Riboli, E, Semple, RK, Stears, A, Cambridge FPLD1 Consortium & EPIC-InterAct Consortium 2017, 'Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance', Nature Genetics, vol. 49, no. 1, pp. 17-26. https://doi.org/10.1038/ng.3714

TY - JOUR

T1 - Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

AU - Lotta, Luca A.

AU - Gulati, Pawan

AU - Day, Felix R

AU - Payne, Felicity

AU - Ongen, Halit

AU - van de Bunt, Martijn

AU - Gaulton, Kyle J

AU - Eicher, John D.

AU - Sharp, Stephen J.

AU - Luan, Jian'an

AU - De Lucia Rolfe, Emanuella

AU - Stewart, Isobel D.

AU - Wheeler, Eleanor

AU - Willems, Sara M

AU - Adams, Claire

AU - Yaghootkar, Hanieh

AU - Sharp, Stephen J.

AU - Forouhi, Nita G.

AU - Kerrison, Nicola D.

AU - Sims, Matt

AU - Lucarelli, Debora M E

AU - Deloukas, Panos

AU - McCarthy, Mark I.

AU - Arriola, Larraitz

AU - Balkau, Beverley

AU - Barricarte, Aurelio

AU - Boeing, Heiner

AU - Franks, Paul W.

AU - Gonzalez, Carlos

AU - Grioni, Sara

AU - Kaaks, Rudolf

AU - Key, Timothy J

AU - Navarro, Carmen

AU - Nilsson, Peter M.

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Quirós, J Ramón

AU - Rolandsson, Olov

AU - Sacerdote, Carlotta

AU - Salamanca-Fernández, Elena

AU - Slimani, Nadia

AU - Tjonneland, Anne

AU - Tumino, Rosario

AU - Spijkerman, Annemieke M. W.

AU - van der A, Daphne L.

AU - van der Schouw, Yvonne T.

AU - Riboli, Elio

AU - Semple, Robert K

AU - Stears, Anna

AU - Cambridge FPLD1 Consortium

AU - EPIC-InterAct Consortium

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84995459787&partnerID=8YFLogxK

U2 - 10.1038/ng.3714

DO - 10.1038/ng.3714

M3 - Article

C2 - 27841877

AN - SCOPUS:84995459787

SN - 1061-4036

VL - 49

SP - 17

EP - 26

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

Abstract

Subject classification (UKÄ)

UN SDGs

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