Departments of Genetics, Diabetes Mellitus, and Medicine, Yoshiuchi Medical Diabetes Institute, 2-16-41 Kamakurayama, Kamakura City, Kanagawa, 248-0031, Japan,
Acta Diabetol. 2013 Oct;50(5):775-9. doi: 10.1007/s00592-012-0414-1. Epub 2012 Jul 15.
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by insulin resistance and defect of insulin secretion. The worldwide prevalence of T2DM is steadily increasing. T2DM is also significantly associated with obesity, coronary artery disease (CAD), and metabolic syndrome. There is a clear difference in the prevalence of T2DM among populations, and T2DM is highly heritable. Human adaptations to environmental changes in food supply, lifestyle, and geography may have pressured the selection of genes associated with the metabolism of glucose, lipids, carbohydrates, and energy. The insulin receptor substrate-1 (IRS1) gene is considered a major T2DM gene, and common genetic variations near the IRS1 gene were found to be associated with T2DM, insulin resistance, adiposity, and CAD. Here, we aimed to find evidence of selection at the IRS1 gene loci using the HapMap population data. We investigated a 3-step test procedure-Wright's F statistics (Fst), the long-range haplotype (LRH) test, and the integrated haplotype score (iHS) test-to detect selection at the IRS1 gene loci using the HapMap population data. We observed that 1 CAD-associated SNP (rs2943634) and 1 adiposity- and insulin resistance-associated SNP (rs2943650) exhibited high Fst values. We also found selection at the IRS1 gene loci by the LRH test and the iHS test. These findings suggest evidence of selection at the IRS1 gene loci and that further studies should examine the adaptive evolution of T2DM genes.
2 型糖尿病（T2DM）是一种以胰岛素抵抗和胰岛素分泌缺陷为特征的复杂疾病。全球 T2DM 的患病率正在稳步上升。T2DM 还与肥胖、冠心病（CAD）和代谢综合征显著相关。不同人群 T2DM 的患病率存在明显差异，且 T2DM 具有高度遗传性。人类对食物供应、生活方式和地理环境变化的适应可能对与葡萄糖、脂质、碳水化合物和能量代谢相关的基因选择施加了压力。胰岛素受体底物-1（IRS1）基因被认为是 T2DM 的主要基因，IRS1 基因附近的常见遗传变异与 T2DM、胰岛素抵抗、肥胖和 CAD 有关。在这里，我们旨在利用 HapMap 人群数据寻找 IRS1 基因座选择的证据。我们使用 HapMap 人群数据，通过 Wright 的 F 统计量（Fst）、长程单倍型（LRH）检验和整合单倍型得分（iHS）检验，对 IRS1 基因座的选择进行了 3 步测试。我们观察到 1 个与 CAD 相关的 SNP（rs2943634）和 1 个与肥胖和胰岛素抵抗相关的 SNP（rs2943650）表现出较高的 Fst 值。我们还发现 IRS1 基因座存在选择。这些发现表明 IRS1 基因座存在选择的证据，需要进一步研究 T2DM 基因的适应性进化。
