Genetic fine mapping of 39 susceptibility loci — defined by genome-wide association studies — in 27,206 individuals with type 2 diabetes mellitus (T2DM) and 57,574 controls, has identified 49 distinct association signals, predominantly mapping to noncoding sequences. Comparison of these signals with chromatin immunoprecipitation sequence data identified a common role for hepatocyte nuclear factor 3β (HNF-3β, encoded by FOXA2) transcription-factor binding in the regulation of gene activity contributing to disease susceptibility. For example, an allelic variant associated with T2DM risk at the MTNR1B gene had higher HNF-3β transcriptional enhancer activity in human pancreatic islet and liver-derived cells than low-risk alleles. HNF-3β binding patterns could inform strategies for future research into the mechanisms underlying T2DM susceptibility.
References
Gaulton, K. J. et al. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat. Genet. http://dx.doi.org/10.1038/ng.3437
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Phillips, R. Fine mapping reveals regulation at T2DM susceptibility loci. Nat Rev Endocrinol 12, 6 (2016). https://doi.org/10.1038/nrendo.2015.203
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DOI: https://doi.org/10.1038/nrendo.2015.203