| Backgroud:Systemic sclerosis (or systemic scleroderma, SSc) is a complex connective tissue disease characterized by tissue fibrosis, vascular endothelial injury and activation of the immune system. Clinically, it can be divided into two major subtypes:dcSSc and IcSSc. Both subtypes can cause clinical symptomes like pulmonary hypertension, pulmonary fibrosis, kidney crisis and etc. The etiology and pathogenesis is uncertain but studies have shown that genetic factors played an important role. International investigators have identified more than50single nucleotide polymorphisms (SNPs) of candidate genes, but the results are controversial. In recent years, Europe and the United States published a few large-scale genome-wide association study (GWAS) of SSc, and found some new loci and the susceptibile genes in the SSc patients.Purpose:To verify the association of candidate genes and its single nucleotide polymorphisms from previous and GWAS studies to systemic sclerosis in Chinese Han population.Methods:A case-control study was applied in this study. A total of296systemic sclerosis patients, which are from the out patient department of dermatology in the Peking Union Medical College Hospital (PUMCH), and230controls which are from the physical examination center of the PUMCH were enrolled in this study. The genome DNA was extracted from peripheral blood of each subject. The method of MassARRAY (designed by Sequenome) SNP analysis is adopted to detect22SNP loci in14candidate genes. Statistical analysis of both genotype and allele frequencies are done to detect the affection of genes to the susceptibility of SSc.Results:At last22SNP loci in14candidate genes were successfully detected. Four SNP sites were detected to have significant differences in alleles between the disease group and the control group:rs1062292(OR=0.620,95%CI0.413-0.932, p=0.021) in gene RHOB, rs763361(OR=0.757,95%C10.581-0.985, p=0.038) in gene CD226, rs2056626(OR=0.636,95%CI0.439-0.922, p=0.016) in gene CD247, rs6457617(OR=0.743,95%CI0.579-0.953, p=0.019) in gene HLA-DQB1.Two genotype were detected to have significant differences in alleles between the disease group and the control group:CD247-rs763361(0.0489), HLA-DQB1-rs6457617(0.0003). Then we divided case group into two subtypes: dcSSc/IcSSc, two SNP sites were detected to have significant differences in alleles between the dcSSc group and the control group:NOTCH4-rs443198(OR=0.627,95%CI0.426-0.921,p=0.017) and IRF8-rs11642873(OR=2.596,95%CI1.087-6.198,p=0.026); Four SNP sites were detected to have significant differences in alleles between the IcSSc group and the control group:CD226-rs443198(OR=0.549,95%CI0.369-0.815,p=0.003), RHOB-rs1062292(OR=0.491,95%CI0.236-1.018;p=0.050), CD247-rs2056626(OR=0.447,95%C10.223-0.894, p=0.020), HLA-DRA-rs3129882(OR=1.686,95%CI1.139-2.493, p=0.009). Three genotype were detected to have significant differences in alleles between the IcSSc group and the control group:CD226-rs763361(p=0.005)、HLA-DRA-rs3129882(p=0.027)、HLA-DQB1-rs6457617(p=0.034).There were no significant differences between the disease group and the control group in the rest of SNP loci.Conclusion:RHOB, CD226, CD247, HLA-DQB1are probably the susceptible genes to SSc in Chinese Han population.NOTCH4and IRF8are probably the susceptible genes to dcSSc while CD226, RHOB, CD247, HLA-DRA to IcSSc. SSc have high level of genetic heterogeneity. Genes which are confidently identified as the susceptible genes of SSc in other population, such as HLA-DPB1, TNFAIP3, GRB10, FAM167A-BLK, KCNA5, NLRP1, may not be the susceptible genes of SSc in Chinese Han population. Thus GWA study of SSc in Chinese Han population is necessary. |
PDF Full Text Request