Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2009 Sep 30;4(9):e7231. doi: 10.1371/journal.pone.0007231.
Single nucleotide polymorphisms (SNPs) rs7903146 and rs12255372 located within TCF7L2 gene have been identified as the strongest common genetic risk factors for development of type 2 diabetes (T2D). We hypothesized that these genetic variants might increase the risk of T2D through regulation of alternative splicing or expression level of TCF7L2 in human adipose tissue.
METHODOLOGY/PRINCIPAL FINDINGS: Expression of 13 assays detecting alternatively spliced forms of TCF7L2 was measured by quantitative reverse-transcriptase PCR (qRT-PCR) in paired biopsies of omental and subcutaneous adipose tissue from 159 obese individuals (BMI 54.6+/-12.2 kg/m(2)). TCF7L2 expression in both types of adipose tissue was not associated with SNPs rs7903146 and rs12255372, T2D status and blood levels of glucose or glycosylated hemoglobin (HbA1c). Expression of assays "ex12-13", "ex12-14" and "ex13-13a" detecting C-terminal alternative exons of TCF7L2 was higher in subcutaneous compared to omental adipose tissue by 1.46 fold (p = 6.5x10(-15)), 1.41 fold (p = 1.4x10(-9)) and 1.26 fold (p = 4.7x10(-6)) in the control group and by 1.86 fold (p = 1.7x10(-4)), 1.77 fold (p = 7.3x10(-4)) and 1.58 fold (p = 6.1x10(-4)) in the T2D group. A pathway enrichment analysis on transcripts significantly co-expressed with TCF7L2 in a microarray set combined with individual expression assays, suggested tissue-specific roles of TCF7L2 splicing forms in regulation of transcription, signal transduction and cell adhesion.
Expression of TCF7L2 alternatively spliced forms may have different functional roles in omental and subcutaneous adipose tissue but is not associated with SNPs rs7903146 and rs12255372 or T2D status.
单核苷酸多态性（SNPs）rs7903146 和 rs12255372 位于 TCF7L2 基因内，被鉴定为 2 型糖尿病（T2D）发展的最强共同遗传风险因素。我们假设这些遗传变异可能通过调节 TCF7L2 在人脂肪组织中的选择性剪接或表达水平来增加 T2D 的风险。
方法/主要发现：在 159 名肥胖个体（BMI 54.6+/-12.2kg/m(2)）的网膜和皮下脂肪组织配对活检中，通过定量逆转录酶-PCR（qRT-PCR）测量了 13 种检测 TCF7L2 选择性剪接形式的测定的表达。两种类型的脂肪组织中 TCF7L2 的表达与 SNPs rs7903146 和 rs12255372、T2D 状态以及血糖或糖化血红蛋白（HbA1c）水平均无关。与网膜脂肪组织相比，检测 TCF7L2 C 末端选择性外显子的测定“ex12-13”、“ex12-14”和“ex13-13a”的表达分别高出 1.46 倍（p = 6.5x10(-15)）、1.41 倍（p = 1.4x10(-9)）和 1.26 倍（p = 4.7x10(-6)），在对照组中，1.86 倍（p = 1.7x10(-4)）、1.77 倍（p = 7.3x10(-4)）和 1.58 倍（p = 6.1x10(-4)）在 T2D 组中。对微阵列组合中与 TCF7L2 显著共表达的转录本进行的通路富集分析，以及个体表达测定，表明 TCF7L2 剪接形式在转录、信号转导和细胞黏附的调节中具有组织特异性作用。
TCF7L2 选择性剪接形式的表达可能在网膜和皮下脂肪组织中具有不同的功能作用，但与 SNPs rs7903146 和 rs12255372 或 T2D 状态无关。
