Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

被引:486
作者
Saxena, Richa [2 ,3 ]
Hivert, Marie-France [4 ,5 ]
Langenberg, Claudia [6 ]
Tanaka, Toshiko [7 ,8 ]
Pankow, James S. [9 ]
Vollenweider, Peter [10 ]
Lyssenko, Valeriya [11 ]
Bouatia-Naji, Nabila [12 ]
Dupuis, Josee [13 ]
Jackson, Anne U. [14 ]
Kao, W. H. Linda [15 ,16 ,17 ]
Li, Man [15 ]
Glazer, Nicole L. [18 ,19 ]
Manning, Alisa K. [13 ]
Luan, Jian'an [6 ]
Stringham, Heather M. [14 ]
Prokopenko, Inga [20 ,21 ]
Johnson, Toby [22 ]
Grarup, Niels [23 ]
Boesgaard, Trine W. [23 ]
Lecoeur, Cecile [12 ]
Shrader, Peter [4 ]
O'Connell, Jeffrey [24 ]
Ingelsson, Erik [25 ,26 ]
Couper, David J. [27 ]
Rice, Kenneth [28 ]
Song, Kijoung [29 ]
Andreasen, Camilla H. [23 ]
Dina, Christian [12 ]
Koettgen, Anna [15 ]
Le Bacquer, Olivier [12 ]
Pattou, Francois [30 ,31 ]
Taneera, Jalal [11 ]
Steinthorsdottir, Valgerdur [32 ]
Rybin, Denis [33 ]
Ardlie, Kristin
Sampson, Michael [34 ]
Qi, Lu [35 ,36 ]
van Hoek, Mandy [37 ]
Weedon, Michael N. [38 ]
Aulchenko, Yurii S. [39 ]
Voight, Benjamin F. [2 ,3 ]
Grallert, Harald [40 ]
Balkau, Beverley [41 ,42 ]
Bergman, Richard N. [1 ]
Bielinski, Suzette J. [43 ]
Bonnefond, Amelie [12 ]
Bonnycastle, Lori L. [44 ]
Borch-Johnsen, Knut [45 ,46 ]
Boettcher, Yvonne [47 ]
机构
[1] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA
[2] Harvard & Massachusetts Inst Technol, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
[3] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
[4] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA
[5] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[6] Addenbrookes Hosp, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge, England
[7] Medstar Res Inst, Baltimore, MD USA
[8] NIA, Clin Res Branch, Baltimore, MD 21224 USA
[9] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
[10] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland
[11] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden
[12] Univ Lille 2, Inst Pasteur, CNRS, Unite Mixte Rech 8090, Lille, France
[13] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
[14] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA
[15] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA
[16] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[17] Johns Hopkins Univ, Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA
[18] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA
[19] Univ Washington, Dept Med, Seattle, WA USA
[20] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England
[21] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
[22] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland
[23] Hagedorn Res Inst, Gentofte, Denmark
[24] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA
[25] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden
[26] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden
[27] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA
[28] Univ Washington, Dept Biostat, Seattle, WA 98195 USA
[29] GlaxoSmithKline Inc, Drug Discovery, Genet, King Of Prussia, PA USA
[30] Univ Lille Nord France, INSERM, Lille, France
[31] Ctr Hosp Reg & Univ Lille, F-59037 Lille, France
[32] deCODE Genet, Reykjavik, Iceland
[33] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA
[34] Norfolk & Norwich Univ Hosp Natl Hlth Serv Trust, Dept Endocrinol & Diabet, Norwich, Norfolk, England
[35] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA
[36] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA
[37] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands
[38] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England
[39] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, NL-3000 DR Rotterdam, Netherlands
[40] Helmholtz Zentrum Muenchen, Inst Epidemiol, Neuherberg, Germany
[41] INSERM, Villejuif, France
[42] Univ Paris 11, Orsay, France
[43] Mayo Clin, Coll Med, Rochester, MN USA
[44] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA
[45] Steno Diabet Ctr, Copenhagen, Denmark
[46] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark
[47] Univ Leipzig, Dept Med, Leipzig, Germany
[48] UCL, Dept Epidemiol & Publ Hlth, London, England
[49] Univ So Calif, Keck Sch Med, Div Endocrinol, Dept Med, Los Angeles, CA 90033 USA
[50] Wellcome Trust Sanger Inst, Cambridge, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
FASTING PLASMA-GLUCOSE; GASTRIC-INHIBITORY POLYPEPTIDE; GLUCAGON-LIKE PEPTIDE-1; BETA-CELL FUNCTION; ASSOCIATION; RISK; RECEPTOR; SENSITIVITY; EXPRESSION; VARIANTS;
D O I
10.1038/ng.521
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2- h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
引用
收藏
页码:142 / U75
页数:9
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