Sanghera D K, Nath S K, Ortega L, Gambarelli M, Kim-Howard X, Singh J R, Ralhan S K, Wander G S, Mehra N K, Mulvihill J J, Kamboh M I
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Ann Hum Genet. 2008 Jul;72(Pt 4):499-509. doi: 10.1111/j.1469-1809.2008.00443.x. Epub 2008 Apr 7.
Recently, the transcription factor-7-like 2 (TCF7L2) gene has been identified as the most important type 2 diabetes mellitus (T2DM) susceptibility gene. Common intronic polymorphisms in this gene have been found to be strongly associated with T2DM susceptibility showing marked reproducibility in multiple populations. The purpose of this study was to confirm the reported association of six TCF7L2 variants in a Khatri Sikh diabetic sample from North India. We genotyped six-associated SNPs in a case-control sample consisting of 556 T2DM cases and 537 controls. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels. We report replication of association of four of the six SNPs with T2DM in this Khatri Sikh sample [rs7903146, (p = 0.010); rs11196205, (p = 0.011); rs10885409, (p = 0.002) and rs4918789, (p = 0.029)], under a dominant model conferring odds ratios (ORs) of 1.39, 1.44, 1.57 and 1.36, respectively. Haplotype analysis provided further evidence of association by showing a significant difference between cases and controls as revealed by the global omnibus test (chi(2)= 19.36; p = 0.0036). Multiple linear regression analysis also revealed the risk allele carriers of three of four significant SNPs (rs7903146, rs11196205, rs10885409) to be significantly associated with increased fasting total cholesterol (p value = 0.019, 0.025, 0.006) and LDL cholesterol levels (p value = 0.021, 0.018, 0.005), respectively. Our findings confirm that the TCF7L2 gene is a major risk factor for development of T2DM in Khatri Sikhs. It also provides new information about the significant impact of TCF7L2 gene variants on plasma cholesterol levels that appear to be independent of BMI.
最近，转录因子7样2（TCF7L2）基因已被确定为2型糖尿病（T2DM）最重要的易感基因。该基因常见的内含子多态性已被发现与T2DM易感性密切相关，在多个群体中表现出显著的重复性。本研究的目的是在来自印度北部的卡特里锡克族糖尿病样本中证实所报道的6个TCF7L2变体的关联性。我们在一个由556例T2DM病例和537例对照组成的病例对照样本中对6个相关的单核苷酸多态性（SNP）进行了基因分型。我们还研究了这些变体对体重指数（BMI）、腰臀比（WHR）、空腹胰岛素以及血糖和血脂水平的影响。我们报告在这个卡特里锡克族样本中，6个SNP中的4个与T2DM的关联性得到了重复验证[rs7903146，（p = 0.010）；rs11196205，（p = 0.011）；rs10885409，（p = 0.002）和rs4918789，（p = 0.029）]，在显性模型下，优势比（OR）分别为1.39、1.44、1.57和1.36。单倍型分析通过全局综合检验显示病例组和对照组之间存在显著差异（卡方 = 19.36；p = 0.0036），进一步提供了关联证据。多元线性回归分析还显示，4个显著SNP中的3个（rs7903146、rs11196205、rs10885409）的风险等位基因携带者分别与空腹总胆固醇升高（p值 = 0.019、0.025、0.006）和低密度脂蛋白胆固醇水平升高（p值 = 0.021、0.018、0.005）显著相关。我们的研究结果证实，TCF7L2基因是卡特里锡克族人患T2DM的主要危险因素。它还提供了关于TCF7L2基因变体对血浆胆固醇水平有显著影响的新信息，这种影响似乎独立于BMI。
