Association Study On The Haplotypes And Genetic Polymorphisms Of Interleukin-1 With Rheumatoid Arthritis

Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with approximately 1 % of prevalence that primarily affects peripheral joints by inducing synovial inflammation, which leads to cartilage destruction, bone erosion, and ultimately causes joint deformity and dysfunction. The etiopathogenisis of RA, which has been unclear so far, is generally known to relate to genetic factors, infection (such as bacteria and virus), destruction of autoimmune tolerance, dyscrinism and others (such as cold, moisture, tiredness, external injury, smoking and stimulus). RA was observed to have a tendency towards family aggregation, as the morbidity of RA was up to 30% in monovular twins, 5% in non-identical twins, which demonstrated the occurrence of RA associated to genetic factors. Interleukin-1 (IL-1), as one of pivotal cytokines in mediating inflammation, can initialize and accelerate the occurrence and development of RA, however, interleukin-1 receptor antagonist (IL-1Ra), a native response factor in body, can effectively block its effects; moreover, the subsequent clinical practices that the recombinant IL-1Ra had successfully healed. RA further verified the occurrence and development of RA was regulated by the balance of IL-1 and IL-1Ra in body. It was found that the balance between IL-1 and IL-1Ra in local tissues plays an important role in the susceptibility to and severity of many diseases. Because the blood plasma level of IL-lRa was co-regulated by the genetic polymorphisms of IL-1Ra and IL-1 3 genes ( IL-1RN and IL-1B), many researchers have studied the association of two single nucleotide polymorphisms at positions -511 and +3954 of the IL-1βgene and a variable number of tandem repeat polymorphism in the second intron of the interleukin-1 receptor antagonist gene with RA susceptibility, but no consistent conclusion has been reached. Since RA is a kind of polygene disease with genetic predisposition, the different degree mutation of hereditary feature could result from different ethnic group and region even individual. So, in the present study, we would carry out a case-control study to observe the distributions of genetic polymorphisms of IL-1 and to evaluate the genetic associations of them with increased risk of Rheumatoid Arthritis in population from Northwest China.Methods 240 patients with RA and 227 matched healthy controls from Northwest China were investigated by using polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. The analysis of their genotype and allele distributions and haplotype construction were performed. In addition, the genetic polymorphisms of three IL-1 genes in Northwest Chinese were compared with those of North American Caucasians and Taiwan Chinese populations.Results The genotype and allele distributions of IL-1B+3954 and IL-IRN polymorphisms were different in RA patients compared with the controls (p < 0.001, 0.001; p=0.028, 0.023, respectively). Three significant differences were also observed in the haplotypes of IL-1B-511C/+3954C/IL-1RNV, IL-1B-511C/+3954T/IL-1RN*1 and IL-1B-511T/+3954T/IL-1RN*1 (p=0.017, 0.030, 0.029; OR=0.721, 2.111, 2.909; 95%CI=0.551-0.944, 1.060-4.204, 1.066-7.902, respectively) between RA and control groups. In addition, the results stratified to the subjects by gender showed that the significant associations of IL-lB+3954 and IL-IRN polymorphisms as well as the IL-1B-511C/+3954T/IL-1RN*1 haplotype with RA mainly resulted from female subjects, while the IL-1B-511T/+3954C/IL-1RN*2 haplotype was observed different to controls in female (p=0.004, OR=2.932, 95%CI=1.375-6.251) . In male subjects, the haplotype of IL-1B-511T/+3954T/IL-1RN*1 was also associated with increased risk of RA (p=0.030, OR=1173.4, 95%CI=65.84-20914), moreover, it had higher risk of Ra in male than female (p=0.016, OR=6.019, 95%CI=1.145-31.65). The results of the IL-1 genetic polymorphisms in three populations showed that the genotype and allele distributions of IL-1B-511, IL-1B+3954 and IL-1RN polymorphisms in Northwest Chinese were different compared with North American Caucasians (p < 0.001, 0.001; p< 0.001, 0.001), but compared with Taiwan Chinese, the genotype and allele distributions of only IL-1B+3954 polymorphism were different (P=0. 002, 0.001) .Conclusion These findings suggested that the IL-1B+3954 and IL-1RN genetic polymorphisms are associated with significantly increased risk of RA in female Chinese population, and the polymorphic site of IL-1 +3954 gene may be developed as a target of molecular drug or a biomarker of molecular diagnosis of RA. The genetic polymorphisms of IL-1 gene in Northwest Chinese with own feature is close to Taiwan Chinese, but different from North American Caucasians. The haplotypes of IL-1B-511C/+3954T/IL-1RN*1, IL-1B-511T/+3954T/IL-1RN*1 and IL-1B-511T/+3954C/IL-1RN*2 have high risks of RA in female Chinese population; but, with regard to the IL-1B-511T/+3954T/IL-1RN*1 haplotype, the male carriers may have higher risk of RA than the female ones. Beside these, the results of stratified analysis to the subjects also imply that sex hormones may affect the expression of IL-1 gene family.