Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study

摘要

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response.Materials and methodsTo test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response.ResultsLogistic regression analyses showed that carriers of the IL4(rs2070874T) and IL4(rs2243250T) and IL8RB(rs1126580A) alleles or the IL8RB(rs2230054C/C) genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNG(rs2069705C) allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075).ConclusionsOur data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.