Structural and Functional Analysis of DNA-repair Gene Variants (XRCC1, ERCC2/XPD) and their Relevance to Chronic Kidney Disease Pathogenesis

Background: According to statistics, chronic kidney disease (CKD) is the fourth leading cause of death in the world and its rate of 4.32% of total deaths in Iraq. Over the past few years, several single -nucleotide polymorphisms (SNPs) have been recognized to be associated with increased risk for CKD.Objectives: To computationally evaluate the impact of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in the coding regions of the XRCC1 and XPD genes using multiple predictive tools.Materials and Methods: Several prediction methods and in silico theoretical models were used to examine non-synonymous SNPs in the XRCC1 and XPD genes. It has been demonstrated that the structure and function of the XRCC1 and XPD proteins, which are involved in deoxyribonucleic acid (DNA) repair, are affected by potentially harmful mutations rs25487, rs1799782, rs13181, and rs1799793.Results: High-confidence three-dimensional structures of the human XRCC1 and XPD proteins were produced using the SWISS-MODEL platform. Mutant models with missense variations (rs25487, rs1799782, rs13181, and rs1799793) exhibited striking changes in protein stability and structure. Several variations have been shown to negatively impact protein function by in silico prediction techniques (i-Mutant, PolyPhen-2, PROVEAN, and SNPs and GO), with rs1799793 exhibiting the highest correlation with illness. The discussed polymorphisms appear to be highly relevant to DNA repair and genomic stability, a conclusion supported by additional analysis of protein–protein interactions, evolutionary conservation within and outside the species, as well as protein classification.Conclusion: Our conclusion was that the rs1799793 variant impacted on the CKD. While the rs13181 polymorphism has shown protein stability increases, the others, including rs25487 and rs1799782 have shown decreases in their stability. Prediction tools (i-Mutant, PolyPhen-2, PROVEAN and SNPs&GO) indicated that XPD variants were generally benign, while the impact of XRCC1 variants could be deleterious.