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)).

Figure 1

Regional plots of five genome-wide significant associations for 2 hour glucose based on 2 hour glucose discovery analysis adjusted for age, sex, BMI and study-specific covariates. (a–e) For each of the GCKR (a), ADCY5 (b), TCF7L2 (c), VPS13C (d) and GIPR (e) regions, directly genotyped and imputed SNPs are plotted with their meta-analysis P values (as −log₁₀ values) as a function of genomic position (NCBI Build 36; hg 18). In each panel, the SNP taken forward for replication (large red diamond) and joint discovery and replication P value (blue diamond) are shown. Estimated recombination rates (HapMap) are plotted to reflect the local linkage disequilibrium structure around the associated SNPs and their correlated proxies (0 < r² < 1, represented on a white to red scale, based on pairwise r² values from HapMap CEU). Gene annotations were taken from the UCSC genome browser.

Figure 2

Percent incretin effect in the Botnia, Denmark and EUGENE2-Kuopio studies of nondiabetic individuals (n = 804) by GIPR rs10423928 genotype. Mean and s.d. for each study are displayed by genotype (see Supplementary Table 5 for details). Incretin effect was adjusted for age, sex and BMI and study-specific covariates.

Figure 3

mRNA expression in human tissues of the genes located in the GIPR (a) and VPS13C (b) regions. Expression data is relative expression levels measured by quantitative RT-PCR. All samples were run in triplicate and normalized to the GAPDH relative expression level. AU, arbitrary units.