A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese.
A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese.
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DOI：
10.1371/journal.pgen.1000847
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发表时间：
2010-02-19
期刊：
影响因子：
4.5
通讯作者：
Wu JY
中科院分区：
文献类型：
--
作者：
Tsai FJ;Yang CF;Chen CC;Chuang LM;Lu CH;Chang CT;Wang TY;Chen RH;Shiu CF;Liu YM;Chang CC;Chen P;Chen CH;Fann CS;Chen YT;Wu JY
为了研究 T2D 发病机制的潜在机制，我们在中国汉族人群中寻找增加 2 型糖尿病 (T2D) 风险的糖尿病易感基因。进行了一项两阶段全基因组关联 (GWA) 研究，其中使用 Illumina HumanHap550-Duo BeadChip 对 995 名患者和 894 名对照进行了第一个基因组扫描阶段的基因分型。这在第 2 阶段的 1,803 名患者和 1,473 名对照中得到了进一步复制。我们在 D 型蛋白酪氨酸磷酸酶受体 (PTPRD) 基因及其周围发现了两个先前与糖尿病易感性无关的位点（P = 8.54×10−10；比值比 [OR] = 1.57；95% 置信区间[CI] = 1.36–1.82）和丝氨酸消旋酶（SRR）（P = 3.06×10−9；OR = 1.28；95% CI = 1.18–1.39）。我们还证实，KCNQ1 的变异与 T2D 风险相关，其中 rs2237895 信号最强（P = 9.65×10−10；OR = 1.29，95% CI = 1.19–1.40）。通过在中国汉族人群中鉴定出两个新的遗传易感性位点，并确认 KCNQ1 的参与（之前报道 KCNQ1 与日本和欧洲血统人群中的 T2D 相关），我们的结果可能有助于更好地了解不同人群中 T2D 分子发病机制的差异。 2 型糖尿病 (T2D) 是一种复杂的疾病，涉及许多基因和环境因素。迄今为止，全基因组和候选基因关联研究已确定至少 19 个区域含有可能带来 T2D 风险的基因。然而，这些研究大多数是针对欧洲血统的患者进行的。我们研究了中国的 T2D 患者，并鉴定了两个基因：PTPRD 和 SRR，这两个基因以前并不知道与糖尿病有关，而且所涉及的生物学途径与之前协会报告中涉及的 T2D 所涉及的生物学途径不同。 PTPRD 是一种蛋白酪氨酸磷酸酶，可能影响其靶细胞上的胰岛素信号传导。 SRR 编码丝氨酸消旋酶，可从 L-丝氨酸合成 D-丝氨酸。 D-丝氨酸（共激动剂）和神经递质谷氨酸都与 NMDA 受体结合并触发大脑中的兴奋性神经传递。谷氨酸信号传导还调节胰岛中的胰岛素和胰高血糖素分泌。因此，SRR 和 D-丝氨酸除了调节胰岛素和胰高血糖素分泌外，还可能在 T2D 的病因学中发挥作用。我们的研究表明，在不同的患者群体中，不同的基因可能会带来患糖尿病的风险。我们的发现可能有助于更好地了解 T2D 的分子发病机制。
To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations. Type 2 diabetes (T2D) is a complex disease that involves many genes and environmental factors. Genome-wide and candidate-gene association studies have thus far identified at least 19 regions containing genes that may confer a risk for T2D. However, most of these studies were conducted with patients of European descent. We studied Chinese patients with T2D and identified two genes, PTPRD and SRR, that were not previously known to be involved in diabetes and are involved in biological pathways different from those implicated in T2D by previous association reports. PTPRD is a protein tyrosine phosphatase and may affect insulin signaling on its target cells. SRR encodes a serine racemase that synthesizes D-serine from L-serine. Both D-serine (coagonist) and the neurotransmitter glutamate bind to NMDA receptors and trigger excitatory neurotransmission in the brain. Glutamate signaling also regulates insulin and glucagon secretion in pancreatic islets. Thus, SRR and D-serine, in addition to regulating insulin and glucagon secretion, may play a role in the etiology of T2D. Our study suggests that, in different patient populations, different genes may confer risks for diabetes. Our findings may lead to a better understanding of the molecular pathogenesis of T2D.
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