Lehman Donna M, Hunt Kelly J, Leach Robin J, Hamlington Jeanette, Arya Rector, Abboud Hanna E, Duggirala Ravindranath, Blangero John, Göring Harald H H, Stern Michael P
Department of Medicine/Clinical Epidemiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Diabetes. 2007 Feb;56(2):389-93. doi: 10.2337/db06-0860.
TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2. We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels (P = 0.001-0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis (P = 4.2 x 10(-5), relative risk [RR] 0.69; P = 6.7 x 10(-6), respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 (P = 0.02, RR 1.64). These data provide evidence that variation in the TCF7L2 genomic region may affect risk for type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in Caucasian populations.
根据Wnt信号通路的指示，TCF7L2既作为基因的阻遏物又作为反式激活因子发挥作用。最近，在三个白种人队列中观察到位于TCF7L2基因单倍型块内的几个高度相关的序列变异与2型糖尿病相关。我们之前在圣安东尼奥家族糖尿病研究（SAFADS）队列中报道了2型糖尿病的连锁关系，该队列由墨西哥裔美国人的扩展家系组成，与包含TCF7L2的10号染色体区域相关。因此，我们对545名SAFADS受试者（178名糖尿病患者）中该基因九个单倍型块的11个单核苷酸多态性（SNP）进行了基因分型，以研究它们在糖尿病发病机制中的作用。我们观察到三个单倍型块中的四个SNP（rs10885390、rs7903146、rs12255372和rs3814573）与2型糖尿病、诊断年龄和2小时血糖水平之间存在名义上的关联（P = 0.001 - 0.055）。此外，我们鉴定出由这四个SNP定义的一种常见保护单倍型，它与2型糖尿病和诊断年龄显著相关（P = 4.2×10⁻⁵，相对风险[RR] 0.69；分别为P = 6.7×10⁻⁶），以及一种赋予糖尿病风险的单倍型，其在SNP rs10885390和rs12255372处包含罕见等位基因（P = 0.02，RR 1.64）。这些数据提供了证据，表明TCF7L2基因组区域的变异可能影响墨西哥裔美国人患2型糖尿病的风险，但可归因风险可能低于白种人群。
