Genotype and tissue-specific effects on alternative splicing of the transcription factor 7-like 2 gene in humans.

The Journal of Clinical Endocrinology and Metabolism
Ashis K MondalSteven C Elbein

Abstract

Noncoding single-nucleotide polymorphisms (SNPs) within the TCF7L2 gene are confirmed risk factors for type 2 diabetes, but the mechanism by which they increase risk is unknown. We hypothesized that associated SNPs alter TCF7L2 splicing and that splice forms have altered biological roles. Splice forms and 5' and 3' untranslated regions were characterized in sc adipose, muscle, liver, HepG2 cells, pancreas, and islet. Isoform-specific transcript levels were quantified in sc adipose. Alternative splice forms were characterized in HepG2 liver cells under glucose and insulin conditions and in SGBS cells with differentiation. Major isoforms were characterized by transfection. The study was conducted at an ambulatory general clinical research center. PATIENTS included 78 healthy, nondiabetic study subjects characterized for insulin sensitivity and secretion. We identified 32 alternatively spliced transcripts and multiple-length 3' untranslated region transcripts in adipose, muscle, islet, and pancreas. Alternative exons 3a, 12, 13, and 13a were observed in all tissues, whereas exon 13b was islet specific. Transcripts retaining exons 13 and 13a but not total TCF7L2 transcripts were significantly correlated with both obesity measures (...Continue Reading

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