Association and in silico studies of ENPP1 gene variants with type 2 diabetes mellitus in a Northern Iranian population

In the current study, a sample population of Northern Iranians was selected to investigate the association of K121Q, rs1799774, rs7754561, and rs997509 ENPP1 gene variants and their haplotypes with T2DM. Genomic DNAs of 978 samples were extracted by Salting Out standard technique and then genotyped by the TaqMan assay. The results show significant differences between study groups for K121Q (p = 0.0004) under a Dominant and rs7754561 (p = 0.002) under a co-dominant hereditary model. Based on allele frequency, there was a significant difference between two study groups at K121Q and rs7754561 variants (p = 0.010 and p = 0.01, respectively). There was no evidence for an association between ENPP1 haplotypes and overall risk of T2DM. Genotype-phenotype sub-analyses showed no significant relationship of four studied polymorphisms with age, gender, FBS, and systolic and diastolic blood pressures. Homology modeling and molecular docking of ENPP1 in K173 and Q173 models with ATP, AMP, and 2'3'-cGAMP as ligands revealed that all ligands had a more binding affinity to Lys173 protein model, and 2'3'-cGAMP had a higher affinity to both ENPP1 protein models compared to ATP and AMP. These findings suggest that ENPP1 gene variants may have a potential impact on the occurrence of T2DM in Northern Iranians.