Alternative splicing of TCF7L2 gene in omental and subcutaneous adipose tissue and risk of type 2 diabetes.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. prokuninal@mail.nih.gov
Ludmila
L
Prokunina-Olsson
Lee M
LM
Kaplan
Eric E
EE
Schadt
Francis S
FS
Collins
D000328:Adult; D017398:Alternative Splicing; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D006031:Glycosylation; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D009852:Omentum / Q000378:metabolism*; D012306:Risk; D050151:Subcutaneous Fat / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein