Daniela Pereira, Lídia Coura and Marcelo Luizon

Nicotinamide phosphoribosyltransferase (NAMPT) is a potential therapeutic biomarker or target for several diseases. NAMPT is activated by Metformin, the first-line therapy for type 2 diabetes, and it is also used as a treatment for other diseases. Moreover, the single nucleotide polymorphism (SNP) rs1319501 in NAMPT promoter region were found to be associated with plasma NAMPT levels, and tightly linked with the SNPs rs9770242 and rs61330082, which are located ~1,500bp upstream from the NAMPT transcription start site. However, these noncoding SNPs may overlap with functional regulatory elements, such as enhancers. Thus, we searched for metformin-responsive regulatory elements in the NAMPT locus, and linked SNPs within them which may be associated with NAMPT levels. First, we examined publicly available ChIP-seq data for active (H3K27ac) and silenced (H3K27me3) histone marks on human hepatocytes treated with metformin, GeneHancer to identify active regulatory elements (enhancers and promoters), and several cis-regulatory elements assignment tools from the Encyclopedia of DNA Elements (ENCODE) to identify enhancers around the NAMPT locus. Next, we performed the functional annotation of noncoding SNPs located in the NAMPT locus using the Genotype-Tissue Expression (GTEx) project data for SNPs linked to NAMPT expression. The SNPs rs1319501, rs9770242 and rs61330082 overlap with a metformin-responsive region enriched for the active histone mark H3K27ac upon metformin treatment, which is located nearby an enhancer element according to GeneHancer (GH07J106288). Interestingly, rs61330082 and rs11977021 were in perfect linkage disequilibrium in a cohort of severely obese children and are associated with visfatin level and adverse cardiometabolic parameters. According to GTEx, these SNPs are eQTLs for NAMPT expression in heart tissue. These data support that noncoding variation within a metformin-activated enhancer may increase NAMPT expression. The perspectives are to functionally characterize these noncoding NAMPT SNPs, which could help to predict NAMPT levels in patients with type 2 diabetes treated with Metformin.

Read More