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1] Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
Nat Commun. 2015 Jan 29;6:5897. doi: 10.1038/ncomms6897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
空腹血糖和胰岛素是2型糖尿病的中间性状。在此，我们通过分析人类外显子芯片上的变异，在60564名非糖尿病个体、16491例2型糖尿病病例和81877名对照中，探讨编码变异对这些性状的作用。我们发现GLP1R基因中一个低频非同义单核苷酸变异（A316T；rs10305492；MAF = 1.4%）与较低的空腹血糖（β=-0.09±0.01 mmol·l⁻¹，P = 3.4×10⁻¹²）、2型糖尿病风险（OR[95%CI]=0.86[0.76 - 0.96]，P = 0.010）、早期胰岛素分泌（β=-0.07±0.035 pmol胰岛素·mmol葡萄糖⁻¹，P = 0.048）相关，但与较高的2小时血糖（β=0.16±0.05 mmol·l⁻¹，P = 4.3×10⁻⁴）相关。我们发现由四个罕见的蛋白质编码单核苷酸变异（H177Y、Y207S、R283X和S324P）驱动，G6PC2基因与空腹血糖存在基于基因的关联（pSKAT = 6.8×10⁻⁶）。我们在ABO基因第一个内含子中位于一个反义长链非编码RNA假定启动子处发现rs651007（MAF = 20%），其与较高的空腹血糖相关（β=0.02±0.004 mmol·l⁻¹，P = 1.3×10⁻⁸）。我们的方法识别出了新的编码变异关联，并扩展了与糖尿病相关定量性状和2型糖尿病易感性相关的变异等位基因谱。
