Association of the genetic polymorphisms in inhibiting and activating molecules of immune system with rheumatoid arthritis: A systematic review and meta‑analysis

Several studies have demonstrated that the genetic polymorphisms in the genes encoding immune regulatory molecules, namely cytotoxic T‑lymphocyte‑associated protein 4 (CTLA4) and CD28, play a fundamental role in susceptibility to rheumatoid arthritis (RA). Several disperse population studies have resulted in conflicting outcomes regarding the genetic polymorphisms in these genes and RA risk. This systematic review and meta‑analysis study was performed to reach a conclusive understanding of the role of single‑nucleotide polymorphisms (SNPs) of CTLA4‑rs231775, CTLA4‑rs5742909, and CD28‑rs1980422 in susceptibility to RA. Databases (ISI Web of Science, MEDLINE/PubMed, and Scopus) were searched to find the case–control studies surveying the association of CTLA4 gene rs231775, CTLA4 gene rs5742909, and CD28 gene rs1980422 polymorphisms and RA susceptibility in different population until August 2020. Association comparison between the polymorphisms and RA proneness was assessed using pooled odds ratio (OR) and their corresponding 95% confidence interval. This study was conducted on 16 population studies, comprising 1078 RA patients and 1118 healthy controls for CTLA4‑rs231775, 2193 RA patients and 2580 healthy controls for CTLA4‑rs5742909, and 807 RA patients and 732 healthy controls for CD28‑rs1980422. Analysis indicated that G‑allele, GG and GA genotypes, and dominant model for rs231775, recessive model for rs5742909, and C‑allele, CC and CT genotypes, and recessive model for rs1980422 were significantly associated with increased RA risk. This meta‑analysis showed that genetic polymorphisms of both immune inhibitory and activating genes, including CTLA4‑rs231775, CTLA4‑rs5742909, and CD28‑rs1980422 polymorphisms, may increase susceptibility to RA.