Genetic variants associated to type 2 diabetes can modulate endocrine enhancers in vivo

Several genome-wide association studies have shown a clear association between single nucleotide polymorphisms (SNPs) and type 2 diabetes, being the vast majority of these variants located in putative endocrine pancreatic enhancers. This suggests that these SNPs may modulate the enhancer activity and, consequently, gene expression. However, the correlation between SNPs and enhancer activity impairment and the in vivo validation are still poorly explored. Here, by using an in vivo mosaic transgenesis assays in zebrafish, Eufrásio and coworkers from Bessa’s lab at I3S, were able to identify 6 endocrine pancreatic enhancers. The risk variant of two sequences decreased enhancer activity, while in another two incremented it. One of the latter, located in a SLC30A8 exon, results in an aminoacid substitution, being the canonical explanation for the risk of type 2 diabetes the decrease of SLC30A8 function. However, there are other studies that show other type 2 diabetes-associated SNPs that truncate SLC30A8 that can confer protection from this disease. The authors clarified this incongruence by showing that the SLC30A8 gain of function, mediated by the presence of one type 2 diabetes-associated SNP, is the explanation for the increased risk for the disease. To know how, read the full work in Diabetes, in the article entitled “In vivo reporter assays uncover changes in enhancer activity caused by type 2 diabetes-associated single nucleotide polymorphisms”.