Candidate Gene Association Analysis Of Systemic Sclerosis In Chinese Han Population

Objective:Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. The result of genome-wide association study (GWAS) showed that the IRF5 and IRF8 gene were associated with SSc in European Caucasian population. The single-nucleotide polymorphisms (SNP) study of candidate gene have related TNFSF4, TNFAIP3, CCR, IRF5, IRF8 and ALK1 polymorphisms to susceptibility for different autoimmune diseases in Caucasian population. Whether the SNP in the TNFSF4, TNFAIP3, CCR, IRF5, IRF8 and ALK1 contribute to the development of SSc in Asians has not been identified. Therefore we sought to explore genetic variants associated with TNFSF4, TNFAIP3, CCR, IRF5,IRF8 and ALK1 in SSc and subphenotype, such as Anti-topoisomerase I positive subphenotype, SSc complicating interstitial lung disease (ILD) subphenotype and SSc complicating pulmonary hypertension (PAH) subphenotype.Methods:The TNFSF4 SNPs (rsl234314, rs2205960, rs12039904 and rs844648), TNFAIP3 SNPs (rs5029939, rs6932056 and rs5029937), CCR6 SNPs(rs3093023, rsl0946216 and rs3093005), IRF5 SNP(rs4728142), IRF8 SNPs(rs11642873 and rsl 1117432) and ALK1 SNP(rs2277382) were genotyped in a cohort of 1030 SSc patients and 1215 healthy controls, using the Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry(MALDI-TOF MS).Results:The rs844648 in TNFSF4 region was significantly associated with SSc in the allelic and genotypic frequencies (p=1.7×10-3and p=5.0×10-3). The allelic frequencies of the rs6932056 in the TNFAIP3 was significant difference between SSc patients and the controls (p=5.0×10-3). Other three TNFSF4 SNPs (rs1234314, rs2205960 and rs12039904) and the TNFAIP3 SNP (rs5029939) demonstrated weak association with SSc for the allelic frequency (p<0.05). In addition, all of the six SNPs were associated with ILD (p<0.05). The rs1234314-rs2205960 haplotypes CG and GT were related to SSc (p=0.024 and p=0.022). The rs12039904-rs844648 haplotypes CG and TA were related to SSc (p=0.005 and p=0.026). The rs3093023 in CCR6 region was significantly associated with SSc in the allelic and genotypic frequencies (p=3.2×10-3and p=7.6×10-3). In addition, the rs3093023 of CCR6 was also especially associated with SSc patients without ILD, PAH and the anti-Scl-70 antibody. The rs3093023-rs 10946216 haplotypes AT and GC were related to SSc (p=8.6×10-3and p=0.03, respectively). The rs4728142 in IRF5 region was significantly associated with SSc in the allelic and genotypic frequencies (p=1.35×10-4and p=1.47×10-4). In addition, the rs4728142 in IRF5 was especially associated with the anti-Scl-70 antibody and ILD (p=2.77×10-4 and p=6.64×10-4). Interestingly, the rs4728142 was also associated with SSc patients without PAH (p=7.7x10-4). The rs2277382 in ALK1 region was significantly associated with SSc patients with PAH (p=7.2×10-3).Conclusion:This was the first study to identify TNFSF4, TNFAIP3, CCR6 and IRF5 polymorphisms were associated with Chinese SSc patients, CCR6 was associated with SSc patients without ILD and PAH, IRF8 was associated with patients without PAH, ALK1 was associated with SSc-PAH in a Chinese Han population, indicating that CCR6, IRF8 and,ALK1 might be susceptibility genes for SSc subphenotypes in Chinese Han population.