Functional mechanisms for type 2 diabetes-associated genetic variants

Aims: Type 2 diabetes (T2D) is a complex endocrine and metabolic disorder, characterized by hyperglycemia due to insulin resistance and relative lack of insulin. Several recent studies have identified a large number of genetic loci associated with T2D without exploring functional mechanisms underlying the associations. This study established integrative analyses to detect the functional mechanisms for T2D-related associations.

Methods: Based on the public available datasets and resources, this study performed integrative analyses (gene relationships among implicated loci (GRAIL), expression quantitative trait loci (eQTL) analysis, differential gene expression analysis and functional prediction analysis) to detect the molecular functional mechanisms underlying the associations.

Results: Two single nucleotide polymorphisms (SNPs) (rs7593730, rs2439312) have been found to act as cis-effect regulators of two corresponding eQTL genes (RBMS1, NRG1) among 252 selected (P<E-4) genetic associations that were archived in the public databases. These two non-HLA genes were also differentially expressed in T2D-related cell groups. The two SNPs were predicted as regulatory sites by utilizing online prediction tools.

Conclusions: This study detected potential regulatory mechanisms underlying the associations between T2D and two identified SNPs. Integrative analysis can be used to provide suggestive clues for the molecular functional mechanisms in T2D.