title: Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.
abstract: 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)).
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
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mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics; D015992:Body Mass Index; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D008297:Male; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism
chemical_list: D054795:Incretins; D007328:Insulin; D011506:Proteins; D012333:RNA, Messenger; D011964:Receptors, Gastrointestinal Hormone; C495324:VPS13C protein, human; C041086:gastric inhibitory polypeptide receptor; D000262:Adenylyl Cyclases; D005947:Glucose