Association Of Gene Polymorphisms Of Interleukin-6 And Interleukin-18 With Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, autoimmunity disease that can leadto severe disabilities and a poor quality of life. Its exact pathogenesis isunknown but genetic and environmental factors play important roles. Althoughnumerous studies reported the association of human leukocyte antigen(HLA)-DRB1*04 and RA, other genes, e.g. cytokines genes, may contributetowards disease susceptibility.Objectives To investigate the single-nucleotide polymorphisms (SNPs)of interleukin-6(IL-6) and interleukin-18(IL-18) gene promoters, and todisclose whether such polymorphisms are associated with susceptibility torheumatoid arthritis(RA) in the Chinese Han population.Methods Four single nucleotide polymorphisms(SNPs) of IL-6 and IL-18gene promoter were detected in 120 patients with rheumatoid arthritis and 168normal controls by using polymerase chain reaction with sequence specificprimers(PCR-SSP) method, including the two sites(-174/-572) of IL-6 and twosites(-607/-137) of IL-18 gene. We measured the serum level of IL-6 and IL-18by enzyme linked immunosorbnent assay test(ELISA).Results Three kind of genotypes were observed at four positions in IL-6and IL-18 gene promoter, and showed that there were the association betweentheir serum levels and the genotypes of IL-6 and IL-18 gene. The significantdifference was observed in the distribution of three genetypes frequenciesat position-174 in the promoter region of IL-6 between RA patients groupsand normal controls (x~2=25.75, P＜0.01),and the frequencies of allele Cat IL-6-174 G/C position is higher than that of allele G (x~2=25.99, P＜0.01, OR=2.26, 95％CI:1.91～2.68). The significant difference was alsoobserved in the distribution of three genotypes frequencies at position-572in the promoter region of IL-6 between RA patients groups and normal controls(x~2=16.14, P＜0.01),and the frequencies of allele G at IL-6-572 C/Gposition is lower than that of allele C (x~2=16.71, P＜0.01, OR=0.51, 95％CI: 0.35～0.74).The significant difference was also observed in thedistribution of three genotypes frequencies at position-607 in the promoterregion of IL-18 between RA patients groups and normal controls (x~2=19.94P＜0.01), and the frequencies of allele A at IL-18-607 C/A position is lowerthan that of allele C (x~2=12.91, P＜0.05, OR=0.70, 95％CI:0.57～0.85). No difference was observed in the distribution of three genotypesfrequencies at position-137 in the promoter region of IL-18 between RApatients groups and normal controls (x~2=3.80, P＞0.05), But the frequenciesof allele C at IL-18-137G/C position is lower than that of allele G (x~2=4.36, P＜0.05, OR=0.69, 95％CI:0.47～1.01).The serum level of theGC+GG genotype was significantly higher than CC genotype in the site ofIL-6-572C/G (P＜0.05),and the serum level of the CC+GC genotype was lowerthan GG genotype in the site of IL-18-137G/C (P＜0.05).At the same time, wealso found that the level of interleukin-6 in serum of RA patients in acuteperiod was significantly higher than the RA patients in stabilize period (P＜0.01). The level of in serum interleikin-6 had significant difference amongthe syndrome patterns of RA patients in acute period (P＜0.05), and the levelof interleukin-6 in in the type of moist and heat gloomy was significantlyhigher than other types in RA patients(P＜0.05). However, the level of inserum interleikin-18 had no significant difference among the syndrome patternsof RA patients in acute period (P＞0.05).Conclusions The polymorpbisms of the promoter region of IL-6 gene areclosely associated with susceptibility to rheumatoid arthritis. And alleleC at position-174 G/C in the promoter of IL-6 gene may be an independentrisk factor. The allele G at position-572 C/G in the promoter of IL-6 geneand allele C at position-137 G/C in the promoter of IL-18 may be the protectivefactors of RA. However, allele A at position-607 C/A in the promoter of IL-18may be not associated with susceptibility to RA. The gene polymorphisms ofIL-6-572C/G and IL-18-137G/C are correlated with their serum level, and thereare the association between IL-6 and the syndrome patterns of RA patients.