TCF7L2

HIGH

Transcription factor 7-like 2

Chromosome: 10q25.2

Gene Overview

TCF7L2 encodes transcription factor 7-like 2, a nuclear effector of the Wnt signaling pathway that regulates gene expression in pancreatic beta cells, intestinal enteroendocrine cells, and hepatic tissues. The gene harbors the strongest common genetic risk variant for type 2 diabetes (rs7903146), with the T allele conferring ~40% increased risk per copy. TCF7L2 influences insulin secretion, incretin response, and hepatic glucose production. Risk variants associate with impaired beta cell function and blunted glucagon-like peptide-1 (GLP-1) response. Expression is highest in intestine, pancreas, and brain. The Wnt/TCF7L2 axis modulates developmental and metabolic gene networks.

Molecular Function

  • Wnt signaling
  • transcriptional regulation
  • DNA binding
  • beta cell function

Protein class: HMG-box transcription factor

Regulatory Annotation

Promoter activity: Wnt-responsive elements; multiple tissue-specific promoters.

Enhancer associations: T2D-associated rs7903146 lies in intron 4; affects chromatin accessibility in pancreatic and intestinal cells.

Methylation sensitivity: Differential methylation at risk locus correlates with T2D.

eQTL tissues: pancreas, liver, adipose tissue

Tissue Expression Context

pancreasTPM range: 15-45GTEx vv8
small intestineTPM range: 20-60GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

TCF7L2 risk variants impair beta cell insulin secretion and incretin responsiveness; reduced Wnt signaling in enteroendocrine L-cells blunts GLP-1 release, contributing to hyperglycemia.

Functional studies show risk allele reduces insulin secretion; GLP-1 receptor agonists partially overcome TCF7L2-associated defect.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Grant SF, et al. (2006). Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genetics. doi:10.1038/ng1732
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.Florez JC, et al. (2006). TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. New England Journal of Medicine. doi:10.1056/NEJMoa062418