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

Objective: To analyze the relationship of genetic polymorphisms in IL1 beta, IL6, TNF-alpha 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% Cl = 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. (C) 2012 Elsevier Ltd. All rights reserved.