The deleterious impact of a non-synonymous SNP on protein structure and function is apparent in hypertension

Abstract

Essential hypertension (EH) is a significant health issue around the globe. The indifferent therapy regimen suggests varied physiological functions due to the lifestyle and genetic presentations of an individual. The endothelial nitric oxide synthase (NOS3) gene is a crucial vascular system marker in EH that contributes significantly to the phenotype. Hence, the present study aimed to employ the candidate gene approach and investigate the association between NOS3 single nucleotide polymorphism (SNP) E298D (G894T/rs1799983) by applying several in silico tools and validation through human samples screening. We corroborated computational findings through a case-control study comprising 294 controls and 299 patients; the 894T allele emerged significantly as the risk allele (odds ratio=2.07; P=6.38E-05). The in silico analyses highlighted the significance of E298D on the native structure and function of NOS3. The dynamics simulation study revealed that the variant type 298D caused structural destabilization of the protein to alter its function. Plasma nitrite levels were reduced in patients (P=0.0002), and the same correlated with the 894T allele. Furthermore, correlations were apparent between clinical, genotype, and routine biochemical parameters. To conclude, the study demonstrated a perceptible association between the SNP E298D and NOS3 protein structure stability that appears to have a bearing on the enzyme's function with a deleterious role in EH.

Keywords: Essential hypertension; Genotyping; Missense SNP; Molecular docking simulations; NOS3.