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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
| Title | Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Kilpeläinen, 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 |
| Journal | Nat Genet |
| Volume | 43 |
| Issue | 8 |
| Pagination | 753-60 |
| Date Published | 2011 Jun 26 |
| ISSN | 1546-1718 |
| Keywords | Adiponectin, 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> |
| DOI | 10.1038/ng.866 |
| Alternate Journal | Nat. Genet. |
| PubMed ID | 21706003 |
| PubMed Central ID | PMC3262230 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States CZB/4/710 / / Chief Scientist Office / United Kingdom N01 HC085086 / HC / NHLBI NIH HHS / United States R01-HL088119 / HL / NHLBI NIH HHS / United States R01 DK075787-05 / DK / NIDDK NIH HHS / United States K23 DK080145 / DK / NIDDK NIH HHS / United States 084723/Z/08/Z / / Wellcome Trust / United Kingdom R01-DK07568102 / DK / NIDDK NIH HHS / United States R01-AG031890-01 / AG / NIA NIH HHS / United States RG/08/008/25291 / / British Heart Foundation / United Kingdom R01 AR046838 / AR / NIAMS NIH HHS / United States N01AG12100 / AG / NIA NIH HHS / United States N1AG62101A / AG / NIA NIH HHS / United States N01-HC15103 / HC / NHLBI NIH HHS / United States P30-DK072488 / DK / NIDDK NIH HHS / United States R01 HL036310 / HL / NHLBI NIH HHS / United States U01 HL080295-04 / HL / NHLBI NIH HHS / United States R01-HL08770003 / HL / NHLBI NIH HHS / United States R01 HL087652-03 / HL / NHLBI NIH HHS / United States G19/35 / / Medical Research Council / United Kingdom N01 AG062101 / AG / NIA NIH HHS / United States SP/04/002 / / British Heart Foundation / United Kingdom U01 HL080295 / HL / NHLBI NIH HHS / United States G20234 / / Biotechnology and Biological Sciences Research Council / United Kingdom N01-HC85079-86 / HC / NHLBI NIH HHS / United States N01 HC075150 / HC / NHLBI NIH HHS / United States G0100222 / / Medical Research Council / United Kingdom U01-HL080295 / HL / NHLBI NIH HHS / United States N01-HC55222 / HC / NHLBI NIH HHS / United States MC_U127561128 / / Medical Research Council / United Kingdom N01-HC75150 / HC / NHLBI NIH HHS / United States G0700931 / / Medical Research Council / United Kingdom N01 HC015103 / HC / NHLBI NIH HHS / United States R01 AR046838-05 / AR / NIAMS NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States / / Medical Research Council / United Kingdom AG13196 / AG / NIA NIH HHS / United States U01 HL084756-03 / HL / NHLBI NIH HHS / United States P30 DK063491-03 / DK / NIDDK NIH HHS / United States N02 HL64278 / HL / NHLBI NIH HHS / United States R01 DK068336 / DK / NIDDK NIH HHS / United States G0802051 / / Medical Research Council / United Kingdom G8802774 / / Medical Research Council / United Kingdom G1000143 / / Medical Research Council / United Kingdom G0902037 / / Medical Research Council / United Kingdom / / Department of Health / United Kingdom R01 AG018728-05S1 / AG / NIA NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States R01 DK075787 / DK / NIDDK NIH HHS / United States M01 RR 16500 / RR / NCRR NIH HHS / United States N01 AG062106 / AG / NIA NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States M01 RR000425-36 / RR / NCRR NIH HHS / United States R01-DK075787 / DK / NIDDK NIH HHS / United States R01 DK075681 / DK / NIDDK NIH HHS / United States R01 AR041398 / AR / NIAMS NIH HHS / United States M01 RR016500-04 / RR / NCRR NIH HHS / United States R01-HL087652 / HL / NHLBI NIH HHS / United States G0601966 / / Medical Research Council / United Kingdom N01HC85086 / HL / NHLBI NIH HHS / United States R01 AG032098-01A1 / AG / NIA NIH HHS / United States R01 AG032098 / AG / NIA NIH HHS / United States K23 DK080145-05 / DK / NIDDK NIH HHS / United States MC_U106179471 / / Medical Research Council / United Kingdom R37 AG013196 / AG / NIA NIH HHS / United States U01 HL084756 / HL / NHLBI NIH HHS / United States R01-AG032098-01A1 / AG / NIA NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 AR041398-19 / AR / NIAMS NIH HHS / United States P30 DK072488 / DK / NIDDK NIH HHS / United States R01-HL036310-20A2 / HL / NHLBI NIH HHS / United States / / Cancer Research UK / United Kingdom N01 HC055222 / HC / NHLBI NIH HHS / United States N01 AG062103 / AG / NIA NIH HHS / United States G0401527 / / Medical Research Council / United Kingdom N01-HC45133 / HC / NHLBI NIH HHS / United States G0701863 / / Medical Research Council / United Kingdom N1AG62103A / AG / NIA NIH HHS / United States U01 HL072515-06 / HL / NHLBI NIH HHS / United States R01-DK06833603 / DK / NIDDK NIH HHS / United States U01 HL072515 / HL / NHLBI NIH HHS / United States M01 RR016500 / RR / NCRR NIH HHS / United States R01-AR/AG41398 / AG / NIA NIH HHS / United States 091746/Z/10/Z / / Wellcome Trust / United Kingdom RG/08/008 / / British Heart Foundation / United Kingdom 095515 / / Wellcome Trust / United Kingdom R01 HL087700-03 / HL / NHLBI NIH HHS / United States N1AG62106A / AG / NIA NIH HHS / United States R01 DK075681-04 / DK / NIDDK NIH HHS / United States U01-HL84756 / HL / NHLBI NIH HHS / United States M01 RR000425 / RR / NCRR NIH HHS / United States R01 HL088119-04 / HL / NHLBI NIH HHS / United States SP/07/007/23671 / / British Heart Foundation / United Kingdom N01HC75150 / HL / NHLBI NIH HHS / United States R01 DK089256 / DK / NIDDK NIH HHS / United States R01 AG013196 / AG / NIA NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States R01 DK068336-03 / DK / NIDDK NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States PG/07/133/24260 / / British Heart Foundation / United Kingdom R01-AR046838 / AR / NIAMS NIH HHS / United States R01-AG18728 / AG / NIA NIH HHS / United States N01-HC25195 / HC / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01 HC085079 / HC / NHLBI NIH HHS / United States R01 HL117078 / HL / NHLBI NIH HHS / United States MC_U106188470 / / Medical Research Council / United Kingdom N01 HC045133 / HC / NHLBI NIH HHS / United States R01 HL087700 / HL / NHLBI NIH HHS / United States 091551 / / Wellcome Trust / United Kingdom 077016/Z/05/Z / / Wellcome Trust / United Kingdom U01-HL72515 / HL / NHLBI NIH HHS / United States R01 AG031890 / AG / NIA NIH HHS / United States P30 DK072488-04S1 / DK / NIDDK NIH HHS / United States R01 AG018728 / AG / NIA NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States K23-DK080145 / DK / NIDDK NIH HHS / United States N01-HC35129 / HC / NHLBI NIH HHS / United States N01-AG12100 / AG / NIA NIH HHS / United States R01 HL088119 / HL / NHLBI NIH HHS / United States RG/07/008/23674 / / British Heart Foundation / United Kingdom |