| Background Rheumatoid arthritis(RA) is a systemic autoimmune disease which is characterized by persistent synovitis and production of auto-antidodies. After diagnosis, timely treatment is needed to prevent progressive joint destruction. Various elements have been implicated in the development of RA, and plenty of studies have suggested that genetic factors play a vital role in the development and progression of this disease. Due to the rapid advancements in genotyping technology and the completion of human genome project, genome-wide association studies(GWASs) have been avaible to explore the role of genetic variation across the whole genome, resulting in tremendous progress in the knowledge of genetic background of complex diseases. To date, a number of GWAS investigating the susceptible genes of RA have been reported and most of them were performed in European and American population. However, there is no GWAS of RA in our Chinese population till 2013. A GWAS conducted in Spanish revealed that KLF12 rs1324913 polymorphism was associated with genetic susceptibility to RA and a previous GWAS performed in United Kingdom found that KLF12 rs1887346 polymorphism was associated with genetic susceptibility to RA, indicating that KLF12 is a susceptible gene of RA. Significant associations between genetic polymorphisms(rs2075876 and rs760426) within AIRE have been detected in a GWAS conducted in Japanese, and rs2075876 polymorphism was associated with the transcript level of this gene.Systemic lupus erythematosus(SLE) is another autoimmne disease, and epidemiological studies indicate that SLE and RA might share common genetic background, and this hypothesis has been validated by many replication studies. A GWAS and multi-stage replication study showed that AFF1 rs340630 polymorphism was associated with the genetic susceptibility to SLE. Notably, rs10865035 polymorphism within AFF3, belonging to the same gene family of AFF1, has been detected to be associated with the genetic susceptibility to RA in Caucasian population. One GWAS performed in Chinese Han population identified ETS1 rs6590330 significantly associated with genetic susceptibility to SLE, and another GWAS conducted in Asian population found that ETS1 rs1128334 was significantly associated with genetic predisposition to SLE, and these two polymorphisms in the same gene are in highly linkage disequilibrium. The polymorphism rs1128334 is located in the 3’-untranslated region(UTR) of ETS1, and allelic expression analysis from peripheral blood mononuclear cells(PBMCs) showed significantly lower expression level from the risk allele, indicating that this polymorphism is a functional SNP.Objective Based on the genetic heterogeneity among different ethnicities and the shared genetic background between RA and SLE, and associations of above-mentioned genetic polymorphisms(KLF12 rs1324913, KLF12 rs1887346, AIRE rs2075876, AIRE rs760426, AFF1 rs340630, AFF3 rs10865035 and ETS1 rs1128334) with genetic susceptibility to RA in a Chinese population has not been reported, this investigation was performed to test whether these genetic polymorphisms were involved in the genetic background of RA in Chinese population, thus providing evidence for the further study of relevant molecular pathogenesis.Methods Case-control study design study was applied. Patients with RA were consecutively recruited from Liu’an People’s Hospital. Diagnosis was determined according to the American College of Rheumatology classification criteria in 1987.The controls were ethnically matched patients admitted to the hospital due to the treatment of trauma in the same hospital, all of whom were without RA and any symptoms or signs of autoimmune diseases. All subjects were self-reported Chinese. EDTA anti-coagulated venous blood samples were collected from all subjects. Genomic DNA was extracted from peripheral blood lymphocytes according to the standard procedures. The genotypes of polymorphisms were determined by the Sna Pshot assay. Both genotypic and allelic frequencies were calculated, and the distribution of genotypic and allelic frequencies between cases and controls was examined by chi-square test. For genotype comparison and association under the genetic model(dominant model and recessive model), the logistic regression analysis was applied to calculate the odds ratios(Ors) and 95% confidence intervals(95%Cis) with adjustment for sex. The Hardy–Weinberg equilibrium(HWE) was evaluated in controls. Data analysis was performed by SPSS11.0 software. A difference at P<0.05 was considered as statistically significant. Bonferroni adjustment was applied for multiple comparisons. Due to seven SNPs were included in the present study, so the corrected significant level was 7.14×10-3.Results A total of 232 RA patients(187 females and 45 males, mean±SD age 48.69±14.18 years) and 313 controls(116 females and 197 males, mean±SD age 47.02±16.34 years) were included in this study. Significant difference in the distribution of sex between RA patients and controls was detected(χ2=102.33,P<0.01), but there is no significant differenc in the average age between case group and control group(t=1.28,P=0.20). No deviation from HWE for all these seven genetic polymorphisms was observed in the control group(KLF12 rs1324913: c2=0.34, P=0.56; KLF12 rs1887346: c2=2.67, P=0.10; AIRE rs2075876: c2=0.11, P=0.74; AIRE rs760426: c2=0.02, P=0.89; AFF1 rs340630: c2=4.20, P=0.04; AFF3 rs10865035: c2=4.76, P=0.03; EST1 rs1128334: c2=2.26×10-3, P=0.95). A significant difference was found for the genotype distribution of AIRE rs2075876 polymorphism between patients with RA and control subjects(χ2=8.22, P=0.02). A significantdifference in the allele distribution of AIRE rs2075876 polymorphism between cases and controls was also detected(A vs. G: χ2=5.30, P=0.02, OR=1.33, 95% CI 1.04-1.69). We also evaluated the association between the minor allele A of AIRE rs2075876 polymorphism and the risk of RA under the dominant and recessive models, and significant evidence was found under the recessive model(A/A + G/A vs. G/G: χ2=7.24, P=7.15×10-3, OR=1.78, 95% CI 1.17-2.70). As to AIRE rs760426 polymorphism, significant difference for the genotype distribution between patients and controls was also found(χ2=6.46, P=0.04). The frequency of the minor allele G of AIRE rs760426 was higher in patients compared with controls(47.8 % versus 42.1 %), and this deviation showed a trend towards significant level(χ2=3.50, P=0.06). The association between the minor allele G of AIRE rs760426 polymorphism with RA risk under the dominant model and the recessive model revealed that significant evidence was detected under the recessive model(G/G vs. G/A + A/A: χ2=5.38, P=0.02, OR=1.73, 95% CI 1.09-2.76). However, only the association betweent A allele of AIRE rs2075876 and RA under dominant model was significant with board-line edidence after the Bonferroni adjustment. Non-significant evidence was detected for the associations of other remaining genetic polymorphisms with genetic predisposition to RA in our study.Conclusion Our results indicated that AIRE rs2075876 and rs760426 polymorphisms were involved in the genetic background of RA in the Chinese population. However, only the association betweent A allele of AIRE rs2075876 and RA under dominant model was significant with board-line edidence after the Bonferroni adjustment.The AIRE gene might be a susceptible of RA in our Chinese population, and studies with larger sample sizes were required to confirm whether AIRE gene was a ture susceptible gene of RA in Chinese. Fine-mapping studies with larger sample sizes are required to further test whether the other remaing genes included in our study are involved in the genetic background of RA in Chinese population. |
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