Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nat Genet. 2010 Feb;42(2):142-8. doi: 10.1038/ng.521. Epub 2010 Jan 17.
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)).
口服葡萄糖耐量试验 2 小时后的血糖水平是用于诊断 2 型糖尿病的临床葡萄糖耐量指标。我们对 9 项全基因组关联研究（n=15234 名非糖尿病个体）进行了荟萃分析，并对 29 个独立位点（n=6958-30620）进行了随访。我们在 GIPR 基因座发现了与 2 小时血糖水平相关的变异(rs10423928，A 等位基因每增加一个，β（s.e.m.）=0.09（0.01）mmol/l，P=2.0×10(-15))。GIPR A 等位基因携带者的胰岛素分泌也减少（n=22492；胰岛素原指数，P=1.0×10(-17)；胰岛素-葡萄糖曲线下面积比值，P=1.3×10(-16)），肠降血糖素效应减弱（n=804；P=4.3×10(-4))。我们还在 ADCY5(rs2877716，P=4.2×10(-16))、VPS13C(rs17271305，P=4.1×10(-8))、GCKR(rs1260326，P=7.1×10(-11))和 TCF7L2(rs7903146，P=4.2×10(-10))基因座发现了与 2 小时血糖相关的变异。在这三个新发现的基因座（GIPR、ADCY5 和 VPS13C）中，只有 ADCY5 在合作研究中被发现与 2 型糖尿病相关（n=35869 例病例，89798 例对照，OR=1.12，95%CI 1.09-1.15，P=4.8×10(-18))。
