Association of DNA damage response pathway genes with rheumatoid arthritis risks: a case-control study

Rheumatoid arthritis (RA) is an autoimmune disease affecting the joints and other extra-articular organs. RA has the symptoms of inflammation, joint dysfunction, and reduction in life expectancy. The main causes of RA are family history, immunogenicity, smoking, and genetic factors. Among the genetic factors, DNA damage response pathway genes are primarily involved in repairing damage caused by smoking and other carcinogens. Studies have reported an increased DNA damage frequency in RA patients. The present study is designed to illuminate the association between the DNA damage response pathway genes (PARP1, TREX1, ATM, and TP53) and RA in the Pakistani population. Methods For this purpose, 500 RA patients and 500 age/gender-matched controls were collected and DNA/RNA was extracted. The genotype frequency of selected SNPs [PARP1 (Val76Ala), ATM (Pro1054Arg), TP53 (Ala138Val), and TREX (Tyr177Tyr)] was measured using the Tetra-ARMS PCR. Expression analysis of selected genes was measured using quantitative PCR. Statistical analysis showed a significantly increased frequency of mutant allele Val76Ala (p < 0.0001), Pro1054Arg (p < 0.0001), Ala138Val (p < 0.0001), and Tyr177Tyr (p < 0.0001) in RA patients compared to controls. Linkage disequilibrium showed a strong linkage disequilibrium between selected SNPs in RA patients compared to controls. Quantitative PCR showed a significant downregulation of PARP1 (p < 0.0001), ATM (p < 0.0001), TP53 (p < 0.0001), and TREX (p < 0.0001) in RA patients. ROC curve analysis showed a good diagnostic value for selected genes in RA patients. The present study showed that increased mutant genotype frequency and expression deregulation of DNA damage response pathway genes was linked with significant increased risk of RA. This study showed that DNA damage response pathway genes can act as efficient/specific diagnostic markers for said disease. Furthermore, these findings also lay a solid foundation for further research based on targeted metabolomics/genomics, which may lead to the development of more effective treatment strategies in the future.