Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
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DOI：
10.2337/db11-0415
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发表时间：
2011-10-01
期刊：
影响因子：
7.7
通讯作者：
Florez, Jose C.
中科院分区：
文献类型：
--
作者：
Strawbridge, Rona J.;Dupuis, Josee;Florez, Jose C.
目的 - 胰岛素原是成熟胰岛素和C肽的前体。较高的循环胰岛素原水平与β细胞功能受损、血糖升高、胰岛素抵抗以及2型糖尿病（T2D）相关。对胰岛素加工途径的研究可能为T2D病理生理学提供新的见解。
研究设计与方法 - 我们对约250万个基因分型或推算的单核苷酸多态性（SNP）与10701名欧洲血统的非糖尿病成年人的空腹胰岛素原水平进行了全基因组关联测试的荟萃分析，并在多达16378人中对23个基因座进行了后续研究，使用了针对年龄、性别、空腹胰岛素以及研究特定协变量进行调整的加性遗传模型。
结果 - 8个基因座的9个SNP与胰岛素原水平相关（P < 5×10⁻⁸）。两个基因座（LARP6和SGSM2）此前未与代谢性状相关，一个（MADD）与空腹血糖相关，一个（PCSK1）与肥胖有关，四个（TCF7L2、SLC30A8、VPS13C/C2CD4A/B和ARAP1，原名CENTD2）增加T2D风险。ARAP1的升高胰岛素原的等位基因与较低的空腹血糖（P = 1.7×10⁻⁴）、改善的β细胞功能（P = 1.1×10⁻⁵）以及较低的T2D风险（比值比0.88；P = 7.8×10⁻⁶）相关。值得注意的是，PCSK1编码蛋白激素原转化酶1/3，它是胰岛素加工途径中的第一种酶。由9个升高胰岛素原的等位基因组成的基因型评分在两个大型病例 - 对照数据集中与冠心病无关。
结论 - 我们已经确定了9种与空腹胰岛素原相关的基因变异。我们的研究结果阐明了人类葡萄糖稳态和T2D发展的生物学基础，并反驳了胰岛素原在冠状动脉疾病发病机制中的直接作用。《糖尿病》60:2624 - 2634, 2011
OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of similar to 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC3OA8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. Diabetes 60:2624-2634, 2011