Conclusions
These results provide a detailed map of cis-regulatory elements within the TCF7L2 GWAS locus and support the hypothesis of cis-regulatory variation leading to type 2 diabetes predisposition. The detection of allelic-specific effects for SNP rs7903146 in multiple cell lines further alludes to the likelihood of a peripheral defect in disease aetiology.
Methods
A systematic cell-based enhancer strategy was employed to interrogate all sequences within the 92 kb type-2-diabetes-association interval for cis-regulatory activity in a panel of cell lines (HCT-116, Neuro-2a, C2C12, U2OS, MIN6 and HepG2). We further evaluated chromatin state at a subset of these regions in HCT-116 and U2OS cells and examined allelic-specific enhancer properties at the type-2-diabetes-associated single nucleotide polymorphism (SNP) rs7903146.
Results
In total, we assigned cis-regulatory activity to approximately 30% (9/28) of constructs tested. Notably, a subset of enhancers was active across multiple cell lines and overlapped with key epigenetic markers suggestive of cis-regulatory sequences. We further replicated the allelic-specific properties for SNP rs7903146 in pancreatic beta cells and additionally demonstrate identical allelic-specific enhancer effects in other cell lines. Conclusions: These results provide a detailed map of cis-regulatory elements within the TCF7L2 GWAS locus and support the hypothesis of cis-regulatory variation leading to type 2 diabetes predisposition. The detection of allelic-specific effects for SNP rs7903146 in multiple cell lines further alludes to the likelihood of a peripheral defect in disease aetiology.