Association of NOS۳-c.۸۹۴G>T transversion with susceptibility to metabolic syndrome in Azar-cohort population: A case-control study and in silico analysis of the SNP molecular effects

Objective(s): We investigated whether NOS۳-c.۸۹۴G>T transversion (rs۱۷۹۹۹۸۳), which causes the substitution of glutamate with aspartate (E۲۹۸D) in the oxygenase domain of endothelial nitric oxide synthase (eNOS), is associated with susceptibility to metabolic syndrome (MetS) risk in Iranian-Azerbaijanis. Materials and Methods: The frequencies of the alleles and genotypes were compared in the ۳۰۰ cases and ۳۰۰ controls using PCR-RFLP assay. Also, higher-order MetS interaction with the genotypes, gender, age, and body mass index (BMI) was evaluated by classification and regression tree (CART) analysis. In silico analysis was done to introduce a hypothesis describing the molecular effects of NOS۳-c.۸۹۴G>T. Results: The T allele (OR:۱.۴۶; CI:۱.۰۵۴-۲.۰۴; P=۰.۰۲), GT genotype (OR:۱.۴۴; CI:۱.۰۲-۲.۰۳; P=۰.۰۳), and dominant model (TT+GT vs GG, OR:۱.۴۸; CI:۱.۰۶-۲.۰۶; P=۰.۰۱) were found to be associated with increased risk of MetS. In the male subpopulation TT genotype (OR:۷.۱۹; CI:۱.۵۳-۳۳.۷۰; P=۰.۰۱) was discovered to be associated with increased odds of MetS. CART analysis showed that NOS۳-c.۸۹۴G>T genotypes and BMI significantly contribute to modulating MetS risk. Furthermore, in silico investigation revealed that c.۸۹۴G>T may alter eNOS function through affecting interactions of its oxygenase domain with proteins such as B۲R, b-actin, CALM۱, CAV۱, GIT۱, HSP۹۰AA۱, NOSIP, and NOSTRIN. Conclusion: We showed that NOS۳-c.۸۹۴G>T was associated with an increased risk of MetS in Iranian-Azerbaijanis, and BMI modulates the effects of NOS۳-c.۸۹۴G>T genotypes on MetS risk. Also, in silico analysis found that NOS۳-c.۸۹۴G>T may affect the interaction of the eNOS oxygenase domain with its several functional partners.

Keywords:

Azar , cohort Bioinformatics Metabolic syndrome Nitric oxide pathway rs۱۷۹۹۹۸۳