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

By R. Saxena, M. Hivert, C. Langenberg, Toshiko Tanaka, James S. Pankow, P. Vollenweider, V. Lyssenko, N. Bouatia-Naji, Josée Dupuis, A. Jackson and 144 more. Nature Genetics, 2010

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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, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 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 × 10−18).

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7fbf9e4a8919128263b6e4ed3d97a652c53766d8

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Citations in the corpus

The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits (2012, methodology): “The Metabochip was designed by representatives of the Body Fat Percentage [9], CARDIoGRAM (coronary artery disease and myocardial infarction) [10], DIAGRAM (type 2 diabetes) [11], GIANT (anthropometric traits) [3,12,13], Global Lipids Genetics (lipids) [4], HaemGen (hematological measures) [14], ICB”
An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans (2017, neutral): “The third cluster, showing marked associations with BMI and lipid levels, included NRXN3, CMIP, APOE, and MC4R but not FTO, which clustered alone.”
Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution (2010, neutral): “We evaluated the 14 WHR-associated loci for their relationships with related metabolic traits using GWAS data provided by trait-specific consortia 19 - 21 as well as our de novo genotyped follow-up studies.”
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes (2012, neutral): “The lead sex-differentiated SNP in GIPR is only weakly correlated with previously reported associations with BMI 15 (CEU r 2 = 0.06) and two-hour glucose levels 33 (CEU r 2 = 0.07) (Supplementary Table 4).”
Pharmacology, physiology, and mechanisms of incretin hormone action. (2013, background): “…subjects with a SNP (rs10423928) in the Gipr gene exhibit reduced islet Gipr mRNA transcripts, secrete less insulin in response to exogenous GIP (240 pmol/kg/hr), and display impaired incretin responses and elevated 2 hr glucose levels during an OGTT (Lyssenko et al., 2011; Saxena et al., 2010).”