Association analysis of single nucleotide polymorphisms of proinflammatory cytokine and their receptors genes with rheumatoid arthritis in northwest Chinese Han population

Abstract Objective To analyze the relationship of genetic polymorphisms in IL1β, IL6, TNF-α genes and their receptors genes with rheumatoid arthritis (RA) for northwest Han Chinese. This study also explores whether there are gene–gene interactions among these genetic polymorphisms. Methods A total of 452 patients with RA and 373 matched healthy controls were enrolled to carry out a case-control study for 16 SNPs of IL1B -511 C > T, IL1B -31 T > C, IL1B +3954 C > T, IL1RN T > C, IL6 -597 G > A, IL6 -572 G > C, IL6 -174 G > C, IL6R -183 G > A, IL6R exon2 T > A, IL6R exon1 A > C, TNFA -863 C > A, TNFA -857 C > T, TNFA -308 G > A, TNFA -238 G > A, TNFR1 -383 A > C and TNFR2 T676G T > G from seven genes. Genotyping for the SNPs was conducted on the RotorGene 6000 PCR platform using in-house high resolution melting (HRM) approaches. Detection correctness was validated through direct sequencing. Generalized multifactor dimensionality reduction (GMDR) analysis was applied to discover likely gene–gene interaction model among the SNPs. Results The results showed that the genotype distributions of TNFA- 308, TNFA -857 and TNFA -863 are significantly different between case and control groups ( P  = 0.016, P  = 0.048 and P  = 0.016, respectively). Carriers of TNFA -857 mutant allele conferred risk to RA (OR = 1.525, 95% CI = 1.157–2.009) while those of TNFA -308 and TNFA -863 mutant alleles conferred protection to RA (OR = 0.459, 95% CI = 0.286–0.739; OR = 0.490, 95% CI = 0.329–0.732). GMDR analysis for the SNPs indicated that gene–gene interaction existed among IL1B -31, IL1RN , IL6 -572, IL6R -183, IL6R -exon1 and TNFA -857. Thirteen of all genotypes of the six SNPs combination were discovered to have significant distribution difference between RA group and the control. Conclusions This study demonstrated that PCR-HRM assay is a highly efficient SNP genotyping method especially for the detection of large-scale samples. The SNPs of TNFA- 308 and TNFA -863 are closely associated with RA susceptibility and that gene–gene interactions may occur among the six SNPs of IL1B -31, IL1RN , IL6 -572, IL6R -183, IL6R -exon1 and TNFA -857 in RA patients from northwest Chinese Han population, especially these SNPs’ combination genotypes CT/TT/CC/GG/AC/CC, CT/TT/GC/AA/AC/CT and CT/CT/CC/GA/AC/CC to show high risk of RA susceptibility in our study.