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Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.

Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
TitleGenetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
Publication TypeJournal Article
Year of Publication2011
AuthorsKilpeläinen, TO, Zillikens, CM, Stančáková, A, Finucane, FM, Ried, JS, Langenberg, C, Zhang, W, Beckmann, JS, Luan, J'an, Vandenput, L, Styrkarsdottir, U, Zhou, Y, Smith, AVernon, Zhao, J-H, Amin, N, Vedantam, S, Shin, S-Y, Haritunians, T, Fu, M, Feitosa, MF, Kumari, M, Halldorsson, BV, Tikkanen, E, Mangino, M, Hayward, C, Song, C, Arnold, AM, Aulchenko, YS, Oostra, BA, Campbell, H, Cupples, AL, Davis, KE, Döring, A, Eiriksdottir, G, Estrada, K, Fernández-Real, JManuel, Garcia, M, Gieger, C, Glazer, NL, Guiducci, C, Hofman, A, Humphries, SE, Isomaa, B, Jacobs, LC, Jula, A, Karasik, D, Karlsson, MK, Khaw, K-T, Kim, LJ, Kivimaki, M, Klopp, N, Kuhnel, B, Kuusisto, J, Liu, Y, Ljunggren, O, Lorentzon, M, Luben, RN, McKnight, B, Mellström, D, Mitchell, BD, Mooser, V, Moreno, JMaria, Männistö, S, O'Connell, JR, Pascoe, L, Peltonen, L, Peral, B, Perola, M, Psaty, BM, Salomaa, V, Savage, DB, Semple, RK, Skaric-Juric, T, Sigurdsson, G, Song, KS, Spector, TD, Syvänen, A-C, Talmud, PJ, Thorleifsson, G, Thorsteinsdottir, U, Uitterlinden, AG, van Duijn, CM, Vidal-Puig, A, Wild, SH, Wright, AF, Clegg, DJ, Schadt, E, Wilson, JF, Rudan, I, Ripatti, S, Borecki, IB, Shuldiner, AR, Ingelsson, E, Jansson, J-O, Kaplan, RC, Gudnason, V, Harris, TB, Groop, L, Kiel, DP, Rivadeneira, F, Walker, M, Barroso, I, Vollenweider, P, Waeber, G, Chambers, JC, Kooner, JS, Soranzo, N, Hirschhorn, JN, Stefansson, K, Wichmann, H-E, Ohlsson, C, O'Rahilly, S, Wareham, NJ, Speliotes, EK, Fox, CS, Laakso, M, Loos, RJF
JournalNat Genet
Volume43
Issue8
Pagination753-60
Date Published2011 Jun 26
ISSN1546-1718
KeywordsAdiponectin, Adiposity, Alleles, Body Fat Distribution, Body Mass Index, Body Weight, Female, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Meta-Analysis as Topic, Metabolome, Obesity, Polymorphism, Single Nucleotide, Subcutaneous Fat
Abstract<p>Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.</p>
DOI10.1038/ng.866
Alternate JournalNat. Genet.
PubMed ID21706003
PubMed Central IDPMC3262230
Grant ListM01-RR00425 / RR / NCRR NIH HHS / United States
CZB/4/710 / / Chief Scientist Office / United Kingdom
N01 HC085086 / HC / NHLBI NIH HHS / United States
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084723/Z/08/Z / / Wellcome Trust / United Kingdom
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SP/04/002 / / British Heart Foundation / United Kingdom
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G20234 / / Biotechnology and Biological Sciences Research Council / United Kingdom
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G0100222 / / Medical Research Council / United Kingdom
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/ / Department of Health / United Kingdom
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