Unique splicing pattern of the TCF7L2 gene in human pancreatic islets
Unique splicing pattern of the TCF7L2 gene in human pancreatic islets
复制标题
DOI：
10.1007/s00125-009-1293-z
复制
发表时间：
2009-05-01
期刊：
影响因子：
8.2
通讯作者：
Renstrom, E.
中科院分区：
文献类型：
--
作者：
Osmark, P.;Hansson, O.;Renstrom, E.
TCF 7 L2基因的内含子变异与2型糖尿病的关联性最强，但这种遗传变异转化为生物学功能改变的机制在很大程度上尚不清楚。一种可能的解释是复杂剪接模式的基因型依赖性差异;然而，这在胰腺或胰岛素靶组织中尚未得到表征。本文详细描述了TCF 7 L2在5种人体组织中的剪接模式，并探讨了其与风险基因型的依赖性。采用RT-PCR和定量实时PCR技术，对非糖尿病个体的胰岛、血淋巴细胞、骨骼肌、皮下和内脏脂肪组织中的TCF 7 L2剪接进行了检测。TCF 7 L2剪接变异体的定位显示了胰岛中的特异性模式，具有四种主要的转录本和可变外显子4和15的高使用率。TCF 7 L2 mRNA的总体浓度在胰岛和脂肪中最高，在血液和肌肉中较低。在rs7903146风险（T）等位基因携带者和非携带者之间没有观察到总体数量或剪接模式的显著差异。然而，外显子4在胰岛中的掺入与血浆HbA（1c）水平呈正相关（r = 0.758; p = 0.018）。TCF 7 L2的剪接存在明显的组织特异性差异，其中包含外显子4和15的形式在胰岛中最丰富。胰岛中外显子4的掺入与HbA（1c）水平相关。需要进一步的实验来确定这种相关性的方向，并且需要更大的队列来明确地解决基因型和胰岛中的剪接之间是否存在关系。
Intronic variation in the TCF7L2 gene exhibits the strongest association to type 2 diabetes observed to date, but the mechanism whereby this genetic variation translates into altered biological function is largely unknown. A possible explanation is a genotype-dependent difference in the complex splicing pattern; however, this has not previously been characterised in pancreatic or insulin target tissues. Here, the detailed TCF7L2 splicing pattern in five human tissues is described and dependence on risk genotype explored.RT-PCR and quantitative real-time PCR were employed to characterise TCF7L2 splicing in pancreatic islets, blood lymphocytes, skeletal muscle and subcutaneous and visceral adipose tissue from non-diabetic individuals.The mapping of TCF7L2 splice variants shows a specific pattern in pancreatic islets, with four predominant transcripts and high usage of the variable exons 4 and 15. The overall concentration of TCF7L2 mRNA is highest in islets and fat and lower in blood and muscle. No significant difference in overall amount or splicing pattern was observed between carriers and non-carriers of the rs7903146 risk (T) allele. However, incorporation of exon 4 in islets correlates positively with plasma HbA(1c) levels (r = 0.758; p = 0.018).There were pronounced tissue-specific differences in the splicing of TCF7L2 with forms containing exon 4 and 15 being most abundant in islets. The incorporation of exon 4 in islets correlated with HbA(1c) levels. Further experiments will be needed to determine the direction of this correlation, and larger cohorts needed to unequivocally resolve whether there is a relationship between genotype and splicing in islets.