Identification of a Regulatory Variant That Binds FOXA1 and FOXA2 at the Type 2 Diabetes GWAS Locus

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GWAS have identified more than 1200 loci contributing to risk of disease, including more than 70 loci associated with type 2 diabetes. With a majority of associated variants localized to non-coding regions of the genome, focus has moved to identifying the functional variants explaining the association signals. One mechanism by which variants may act is to affect activity of enhancer elements regulating target gene expression. In this study, we take advantage of recent advances in genome-wide annotation of human regulatory elements to prioritize candidate functional variants at the CDC123/CAMK1D locus. We identify two T2D-associated variants that overlap predicted regulatory enhancer elements. We demonstrate that one variant, rs11257655, shows allele-specific transcriptional enhancer activity in mammalian cell lines relevant to type 2 diabetes. We also show differential protein-DNA binding suggesting that the rs11257655 type 2 diabetes- risk allele increased transcriptional activity through binding a protein complex that includes FOXA1 and FOXA2. This study demonstrates that genome-wide maps of regulatory elements are a useful resource to guide identification of variants differentially affecting transcriptional activity and provides insight into molecular mechanisms underlying a T2D susceptibility locus.

Vyšlo v časopise: Identification of a Regulatory Variant That Binds FOXA1 and FOXA2 at the Type 2 Diabetes GWAS Locus. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004633
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004633

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