Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women
Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women
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DOI：
10.1007/s00109-006-0108-7
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发表时间：
2006-12-01
影响因子：
4.7
通讯作者：
Talmud, Philippa J.
中科院分区：
文献类型：
--
作者：
Humphries, Steve E.;Gable, David;Talmud, Philippa J.
TCF 7 L2的常见变体编码β细胞表达的转录因子，与2型糖尿病（T2 D）的风险增加密切相关。我们采用前瞻性和病例对照设计研究了这种关联。来自前瞻性NPHSII的共计2，676名健康欧洲白色中年男性（158例在15年监测中发展的T2 D）对两个内含子SNP进行基因分型[rs 7903146（IVS 3C> T）和rs 12255372（IVS 4G> T）]显示出强连锁不平衡（D '= 0.88，p <0.001; R-2=0.76，p < 0.001）。IVS 5 T等位基因频率在健康和T2 D中分别为0.28（95% CI 0.27-0.29）和0.33（0.28-0.39）（p=0.04）。与CC男性相比，CT和TT男性的T2 D校正[年龄、体重指数、收缩压、甘油三酯和C反应蛋白水平]风险比分别为1.65（1.13-2.41）和1.87（0.99-3.53），p < 0.01。糖尿病风险的人群归因分数为17%。在1459例欧洲白色T2 D男性和女性（60%男性）中，T等位基因频率为0.36（0.34-0.38），与NPHSII健康男性相比，CT和TT受试者的T2 D OR分别为1.43（1.24-1.65）和2.11（1.69-2.63），p=< 0.0001。与来自南伦敦的非糖尿病种族匹配受试者相比，在919例T2 D印度亚裔受试者[OR= 1.50（1.14-1.99）和1.64（1.03-2.63）p=0.003]和385例非洲裔加勒比受试者[OR=1.25（0.90-1.75）和1.32（0.74-2.33）p=0.17]中观察到相似的效应。在所有研究中，IVS 4G> T的相关性较弱。两个SNPs之间的连锁不平衡在印度亚洲人中很高（D '= 0.94），但在非洲-加勒比人中弱得多（D'= 0.17），并且在该组中单倍型频率显著不同。这些结果将先前的观察结果扩展到其他种族群体，并强烈证实TCF 7 L2基因型是T2 D发展的主要风险因素。
Common variants of TCF7L2, encoding a beta-cell-expressed transcription factor, are strongly associated with increased risk of type 2 diabetes (T2D). We examined this association using both prospective and case-control designs. A total of 2,676 healthy European white middle-aged men from the prospective NPHSII (158 developed T2D over 15 years surveillance) were genotyped for two intronic SNPs [rs 7903146 (IVS3C > T) and rs12255372 (IVS4G > T)] which showed strong linkage disequilibrium (D'=0.88, p < 0.00 1; R-2=0.76, p < 0.001). The IVS5T allele frequency was 0.28 (95% Cl 0.27-0.29) and 0.33 (0.28-0.39) in healthy and T2D, respectively (p=0.04). Compared to CC men, CT and TT men had an adjusted [for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels] hazard ratio for T2D of 1.65 (1.13-2.41) and 1.87 (0.99-3.53), respectively, p < 0.01. The population attributable fraction for diabetes risk was 17%. In 1459, European white T2D men and women (60% male), T allele frequency was 0.36 (0.34-0.38), and compared to NPHSII healthy men the OR for T2D for the CT and TT subjects was 1.43 (1.24-1.65) and 2.11 (1.69-2.63), respectively p=< 0.0001. A similar effect was observed in 919 T2D Indian Asians [OR= 1.50 (1.14-1.99) and 1.64 (1.03-2.63) p=0.003] and 385 Afro-Caribbean subjects [OR=1.25 (0.90-1.75) and 1.32 (0.74-2.33) p=0.17] compared to non-diabetic ethnically matched subjects from South London. Weaker associations were found for the IVS4G > T in all studies. Linkage disequilibrium between the two SNPs was high in Indian Asians (D'=0.94), but much weaker in Afro-Caribbeans (D'=0.17) and haplotype frequencies differed markedly in this group. These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D.