Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Phoenix, Arizona, USA.
Diabetes. 2010 May;59(5):1276-82. doi: 10.2337/db09-1700. Epub 2010 Feb 25.
Prior genome-wide association and exon array expression studies both provided suggestive evidence that apoptosis signal regulating kinase 1 (ASK1) may influence in vivo insulin action in Pima Indians. Genetic variants in or near ASK1 were analyzed to assess the role of this gene in insulin action and type 2 diabetes.
Genotypic data from 31 variants were used to determine the linkage disequilibrium pattern across ASK1 in Pima Indians. Eight tag SNPs were initially genotyped in 3,501 full-heritage Pima Indians. Replication for association with diabetes was assessed in a second population-based sample of 3,723 Native Americans and the published DIAGRAM study. Quantitative traits were analyzed in 536 nondiabetic Native Americans, and ASK1 expression was examined in skeletal muscle of 153 nondiabetic Native Americans.
Three tag SNPs were associated with type 2 diabetes (rs35898099, P = 0.003, odds ratio [95% CI] 1.27 [1.08-1.47]; rs1570056, P = 0.007, 1.19 [1.05-1.36]; rs7775356, P = 0.04, 1.14 [1.01-1.28]) in the full-heritage Pima Indians. The association with rs35898099 was replicated in a second sample of Native Americans (P = 0.04, 1.22 [1.01-1.47]), while that for rs1570056 was replicated in the DIAGRAM study of Caucasians (Z statistic based P = 0.026; fixed-effect model, 1.06 [1.00-1.12]). The diabetes risk allele for rs1570056 was associated with reduced insulin action as assessed by either HOMA-IR in 2,549 nondiabetic full-heritage Pima Indians (P = 0.027) or a hyperinsulinemic-euglycemic clamp among 536 nondiabetic Native Americans (P = 0.02). Real-time PCR identified a positive correlation between ASK1 expression in skeletal muscle biopsies and in vivo insulin action (P = 0.02, r = 0.23), and the risk allele for rs1570056 was associated with lower ASK1 expression (P = 0.003, r = -0.22).
ASK1 variants may increase susceptibility to type 2 diabetes by decreasing insulin sensitivity via reduced ASK1 expression.
先前的全基因组关联和外显子组表达研究都提供了提示性证据，表明凋亡信号调节激酶 1（ASK1）可能影响皮马印第安人的体内胰岛素作用。分析了 ASK1 内或附近的遗传变异，以评估该基因在胰岛素作用和 2 型糖尿病中的作用。
使用来自 31 个变体的基因型数据来确定皮马印第安人 ASK1 中的连锁不平衡模式。最初在 3501 名全血统皮马印第安人中对 8 个标签 SNP 进行了基因分型。在第二个基于人群的 3723 名美国原住民和已发表的 DIAGRAM 研究中评估了与糖尿病的关联复制。在 536 名非糖尿病的美国原住民中分析了定量特征，并在 153 名非糖尿病的美国原住民中检查了骨骼肌中的 ASK1 表达。
三个标签 SNP 与 2 型糖尿病相关（rs35898099，P = 0.003，优势比[95％CI]1.27[1.08-1.47]；rs1570056，P = 0.007，1.19[1.05-1.36]；rs7775356，P = 0.04，1.14[1.01-1.28]）在全血统皮马印第安人中。 rs35898099 的关联在第二个美国原住民样本中得到了复制（P = 0.04，1.22[1.01-1.47]），而 rs1570056 的关联在高加索人 DIAGRAM 研究中得到了复制（基于 Z 统计量的 P = 0.026；固定效应模型，1.06[1.00-1.12]）。 rs1570056 的糖尿病风险等位基因与胰岛素作用降低相关，这是通过 2549 名非糖尿病全血统皮马印第安人的 HOMA-IR 评估的（P = 0.027）或通过 536 名非糖尿病的美国原住民的高胰岛素正葡萄糖钳夹评估的（P = 0.02）。实时 PCR 鉴定出骨骼肌活检中 ASK1 表达与体内胰岛素作用之间存在正相关（P = 0.02，r = 0.23），rs1570056 的风险等位基因与 ASK1 表达降低相关（P = 0.003，r = -0.22）。
ASK1 变异可能通过降低 ASK1 表达来降低胰岛素敏感性，从而增加 2 型糖尿病的易感性。
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