The Biostatistics Center, George Washington University, Rockville, Maryland, USA.
Diabetes. 2010 Oct;59(10):2672-81. doi: 10.2337/db10-0543. Epub 2010 Aug 3.
Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions.
We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates.
We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09-1.40, P = 7 × 10(-4)). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates.
We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.
全基因组关联研究已经开始阐明 2 型糖尿病的遗传结构。我们研究了通过靶向互补方法鉴定的单核苷酸多态性（SNP）是否会影响糖尿病预防计划（DPP）高危人群的糖尿病发病率，以及它们是否会影响预防干预的效果。
我们选择了之前全基因组关联研究鉴定的与 2 型糖尿病和相关特征相关的 SNP，或与之前与 2 型糖尿病相关的 40 个候选基因中的常见变异相关的 SNP，涉及单基因糖尿病、编码 2 型糖尿病药物靶点或药物代谢/转运酶的 SNP，或参与相关生理过程的 SNP。我们分析了 1590 个 SNP 与 2994 名 DPP 参与者中发生糖尿病的关联及其与二甲双胍或生活方式干预反应的相互作用。我们通过评估假发现率来控制多重假设检验。
我们复制了二甲双胍转运基因 SLC47A1 中变体与二甲双胍反应的关联，并在 AMP 激酶（AMPK）基因 STK11、AMPK 亚基基因 PRKAA1 和 PRKAA2 以及编码另一种二甲双胍转运蛋白的 SLC22A1 中的错义 SNP 中检测到了名义上的相互作用。与糖尿病发病率最显著相关的是 AMPK 亚基基因 PRKAG2（危险比 1.24，95%CI 1.09-1.40，P = 7×10(-4)）。总体而言，有 85 个 SNP 与糖尿病发病率有名义上的关联，91 个和 69 个 SNP 分别与二甲双胍和生活方式干预有名义上的相互作用，这些 SNP 大多不重叠。最低的 P 值与实验范围内 33%的假发现率一致。
我们已经确定了二甲双胍反应的潜在遗传决定因素。这些结果值得在独立样本中进一步证实。
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