Analysis Of Candidate Susceptibility Genes And Causative Mutation In Autoimmune Diseases

Autoimmune disease belong to a kind of disorder, with immune balance defect and inappropriate immune response against healthy body tissue. Studies have indicated that both genetic and environmental factors interacted to affect the initiation and progression of disease. Autoimmune diseases often occur sporadically, while some were shown to be familial aggregation. Accordingly, genetic association analysis and genetic linkage analysis can be applied respectively to verify the susceptibility genes in sporadic form or causative mutations in familial form. In this study, candidate gene association study was conducted in systemic lupus erythematosus (SLE), and whole genome linkage analysis combined with exome sequencing were performed in a large ankylosing spondylitis (AS) family.To test the genetic correlation between candidate susceptibility genes and SLE,748patients and750well matched healthy controls were collected. Further, candidate polymorphism loci in C1qA, IRF7/KIAA1542, IKZF1and STAT4gene were analyzed in this study for their association with SLE or clinical phenotypes of patients. Inconsistent with studies in European population, our results indicated that C1qA gene in Chinese had no genetic susceptibility, suggesting that C1qA gene showed heterogeneity in susceptibility to SLE between different ethnic populations. STAT4gene, on the other hand, had the same disease susceptibility in Chinese population. Therefore, we inferred that STAT4gene may play a fundamental or vital role in SLE pathogenesis among populations. IRF7/KIAA1542gene did not confer genetic susceptibility to SLE in our study, but showed significant association with patients having specific clinical phenotypes, including anti-SSA/SSB antibodies, rheumatoid arthritis and lupus nephritis. The results suggested that SLE patients with different clinical manifestations may have distinct genetic background, and IRF7/KIAA1542gene contributed to SLE possibly by affecting patients’specific sub-phenotype. Additionally, IKZF1genes was identified to be a SLE related gene, but we did not observed genetic correlation to any clinical phenotypes.To localized the disease-causing mutations in this ankylosing spondylitis family, genome-wide linkage analysis and whole exome sequencing analysis were applied. In this study,32family members were involved, and patients were found to show heterogeneous clinical phenotypes. What’s more, genome-wide linkage analysis based on32individuals detected no linkage signal, indicating that genetic heterogeneity existed among the patients. Then, linkage analysis was performed in the subgroups stratified according to the severity or HLA-B27status of the patients, and four disease linked regions were identified. Four patients and one healthy individual in this family were selected for exome sequencing analysis, but no mutations were found to be co-segregating with the disease. While, in linkage region of chromosome6two mutations in TREML2and IP6K3gene were detected only in HLA-B27positive individuals. To assess the genetic contribution of TREML2and IP6K3gene to AS, all coding sequences of these two genes were analyzed in sporadic AS patients as well as healthy controls. The results demonstrated that IP6K3may play no role in the pathogenesis of AS, but TREML2likely has a genetic influence on AS. Detailed function of TREML2protein was not clear. Considering that TREML2’s homologous gene (TREM1, TREM2and TREML1) were identified to participate in the regulation of immune response and process of bone cell differentiation, we supposed that deficiency of TREML2gene may associated with autoimmune response or bone damage in AS patients.In conclusion, our study has identified some autoimmune disease related genes, and it can help to understand the genetic background of autoimmune diseases. At the same time, this study may provide more insights for subsequent analysis about treatment and clinical intervention of autoimmune diseases.