Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata 990-9585, Japan.
Metabolism. 2011 Jun;60(6):815-22. doi: 10.1016/j.metabol.2010.07.033. Epub 2010 Sep 20.
The association of the clusterin (CLU) gene polymorphism (single nucleotide polymorphisms [SNPs] 1-4: rs1532278, rs1532277, rs2279590, and rs2279591, respectively) with type 2 diabetes mellitus was examined using a population of the Funagata study (n [male-female] = 1631 [741:884]; age, 62.0 ± 12.1 years), a Japanese community-based study. Single nucleotide polymorphisms 1 to 3 were significantly associated with hemoglobin A(1c) levels (P = .0154, .0021, and .0006, respectively) and diabetes (.0310, .0170, and .0021, respectively). A case-control association study of SNP 3 with diabetes by multiple logistic regression analysis showed a significant association of genotype AA (the at-risk genotype) with an odds ratio (OR) of 2.33 (P = .0039) independently of age and sex. The association was marginally validated by a study with another Japanese community-based sample, the Takahata Study (n [male-female] = 2.948 [1333:1615]; age, 63.0 ± 10.2 years) (OR, 1.59; P = .0595; χ(2)P = .0264). When the 2 samples were combined, the association became more significant (OR, 1.75; P = .0025). In subjects with the non-at-risk genotypes, the insulin resistance index--homeostasis model assessment of insulin resistance (HOMA-R)--increased significantly (P < .0001) and the insulin secretion index--HOMA-β--appeared to decrease (P = .1803 and .0097, respectively, for the genotypes AG and GG) as the glucose tolerance progressed toward diabetes (normal glucose tolerance to glucose intolerance to diabetes). However, in subjects with the at-risk genotype, HOMA-R and HOMA-β showed a significant increase already in the subjects with normal glucose tolerance (P = .0239 and .0305, respectively); and as the glucose tolerance progressed toward diabetes, HOMA-R stayed approximately the same, whereas HOMA-β decreased significantly (P = .0332). The CLU gene was associated with diabetes, probably through an increase in insulin resistance primarily and through an impairment of insulin secretion secondarily.
该研究使用日本福永研究（n[男-女]=1631[741:884]；年龄，62.0±12.1 岁）人群，对簇集蛋白（CLU）基因多态性（单核苷酸多态性[SNP]1-4：rs1532278、rs1532277、rs2279590 和 rs2279591，分别）与 2 型糖尿病的关联进行了研究。SNP1 到 3 与糖化血红蛋白（HbA1c）水平（P=.0154，.0021 和.0006，分别）和糖尿病（P=.0310，.0170 和.0021，分别）显著相关。通过多元逻辑回归分析对 SNP3 与糖尿病的病例对照关联研究显示，AA 基因型（风险基因型）的优势比（OR）为 2.33（P=.0039），独立于年龄和性别。这项关联在另一个日本社区样本塔原研究（n[男-女]=2.948[1333:1615]；年龄，63.0±10.2 岁）中得到了略微验证（OR，1.59；P=.0595；χ2P=.0264）。当将这两个样本合并时，关联变得更加显著（OR，1.75；P=.0025）。在非风险基因型的受试者中，胰岛素抵抗指数-稳态模型评估的胰岛素抵抗（HOMA-R）显著增加（P<.0001），而胰岛素分泌指数-HOMA-β似乎随着葡萄糖耐量向糖尿病（正常葡萄糖耐量-葡萄糖耐量障碍-糖尿病）的进展而降低（AG 和 GG 基因型的 P 值分别为<.0001 和.0097）。然而，在具有风险基因型的受试者中，HOMA-R 和 HOMA-β 在正常葡萄糖耐量的受试者中已经显著增加（P=.0239 和.0305，分别）；随着葡萄糖耐量向糖尿病进展，HOMA-R 保持不变，而 HOMA-β 显著降低（P=.0332）。CLU 基因与糖尿病有关，可能主要通过增加胰岛素抵抗，其次通过损害胰岛素分泌。
