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

Nat Genet
Authors
Keywords
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)).

Year of Publication
2010
Journal
Nat Genet
Volume
42
Issue
2
Pages
142-8
Date Published
2010 Feb
ISSN
1546-1718
URL
DOI
10.1038/ng.521
PubMed ID
20081857
PubMed Central ID
PMC2922003
Links
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R01 DK078616 / DK / NIDDK NIH HHS / United States
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CZB/4/710 / Chief Scientist Office / United Kingdom
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R01 DK058845 / DK / NIDDK NIH HHS / United States
R01 DK062370-05 / DK / NIDDK NIH HHS / United States
MC_UP_A620_1015 / Medical Research Council / United Kingdom
G0600331 / Medical Research Council / United Kingdom
R01 HL036310 / HL / NHLBI NIH HHS / United States
N01 HC085081 / HC / NHLBI NIH HHS / United States
U01 HL080295-04 / HL / NHLBI NIH HHS / United States
R01 HL087652-03 / HL / NHLBI NIH HHS / United States
G19/35 / Medical Research Council / United Kingdom
P01 CA087969 / CA / NCI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
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G0100222 / Medical Research Council / United Kingdom
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088885 / Wellcome Trust / United Kingdom
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MC_U106188470 / Medical Research Council / United Kingdom
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RG/07/008/23674 / British Heart Foundation / United Kingdom