Study On The Association Between IRF5 Polymorphisms And Rheumatoid Arthritis In Han Population Of Shandong Province And A Meta-Analysis

BackgroundRheumatoid arthritis (RA), a chronic systemic autoimmune disorder featured by inflammatory changes of synovial membrane, is a progressive joint disease that may finally lead to joint deformity and disability. Nowadays, the pathogenesis of RA is still unclear. Recently, great concerns have been raised about the interaction among various inflammatory factors in the onset of RA.MicroRNAs (miRNAs) are a class of endogenous, small and non-coding single-stranded RNAs that regulate gene expression at the post-transcriptional level. It has been well recognized that miRNA plays an important role in the regulation of signal transduction of immune inflammatory factors. The regulatory roles of miRNAs are largely based on silencing the expression of their target genes. Moreover, single nucleotide polymorphism (SNP)s in target genes of miRNA were reported to be related to the disease susceptibility due to interruption of miRNA-target interaction. We hypothesized SNPs in miRNA target genes may contribute to the susceptibility in RA.MiR-155, processed from the 3rd exon of a noncoding RNA transcribed from the B-cell Integration Cluster (BIC) on chromosome 21, is considered to be involved in several inflammatory processes. Moreover, accumulating data suggest that aberrant expression of miRNA-155 is associated with the RA susceptibility. Recently, extensive studies have been conducted to determine the association between RA susceptibility and SNPs of IRF5, one of the target genes of miR-155, such as rs752637. However, the conclusions drawn from these studies remains controversial. In this study, genotyping of rs752637 in RA patients and healthy controls admitted to the Department of Rheumatology at Qilu Hospital of Shandong University and Department of Rheumatology and Immunology, Provincial Hospital Affiliated to Shandong University were performed by high resolution melting (HRM) analysis. Moreover, the genotype distribution and alleles frequencies were compared to investigate their association with RA susceptibility. Finally, meta-analysis was performed to determine the relation between rs752637 polymorphism and RA susceptibility based on the published studies available.ObjectiveThe aim of this study is to investigate the association between miR-155 (mircoRNA-155) target gene single nucleotide polymorphism (SNP) and rheumatoid arthritis (RA) in Han Population of Shandong Province.MethodsTarget gene interferon regulator 5 (IRF5) was identitied by bioinformatics softwares as miRanda, targetScan, etc. TagSNP (rs752637^ rs3807306) were selected from dbSNP.322 RA patients and 412 healthy controls were genotyped by high-resolution melting (HRM). The haplotypes were constructed by SHEsis software. The frequencies of genotype、allele and haplotype were calculated by χ2 to analyzed the difference between two groups. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) level were compared between different genotypes by two-tailed t test, all statistical analysis were performed by SPSS 19.0.ResultsGG genotype of rs752637 was higher in RA group than that of control group (χ2=9.09, P=0.011). Remarkable elevation of G allele frequency of rs752637 was noted in RA group compared with that of control group[χ2=7.12、P=0.008、OR (95%CI)=1.374(1.088～1.736)]. Significant increase of AA haplotype of rs752637 was identified in RA group in comparison with that of control group (χ2=6.553, P=0.010, OR=1.480). Moreover, ESR and RF level of GG genotype were elevated compared with those of GA genotype (P=0.021) and AA genotype in RA group (P =0.040), respectively.2 SNPs (rs752637, rs3807306)is mainly composed of 4 kinds of haplotypes, respectively AC, AA, GC, GA (in the sequence of rs752637 and rs3807306). Among them, the AA haplotype in RA group was significantly higher than healthy control group[χ2=6.553.P=0.010、OR(95%CI)=1.480(1.095～2.002)].Conclusion:The polymorphism of rs752637 in IRF5 which was the target gene of miR-155 is susceptible to RA in Han population of Shandong province. The haplotype AA of 2-SNPs may be associated with the susceptibility of RA. The level of ESR and RF in RA patients was significantly higher in GG genotype of rs752637 than GA and AA genotypes, which implies the association between GG genotype with the clinical activity of RA patients. The rs3807306 genotype and allele frequencies were not statistically significant in the RA group and the healthy control group differences, no significant difference was found between the genotype and the clinical data and laboratory indexes. Rs3807306 may not be associated with RA susceptibility, genotypes and RA disease activity may not exist correlation.