Systemic sclerosis (SSc) and ankylosing spondylitis (AS) are two immune-mediated diseases, the former an autoimmune disease associated with specific alleles of HLA class II DR, DQ and DP, and the latter an autoinflammatory disease associated with HLA class I alleles, most specifically HLA-B27. However, the MHC contribution to neither disease can be fully explained by associations with only these classic HLA alleles. Recent genome-wide association studies (GWAS) conducted by us have shown that the strongest disease-association loci fall within the major histocompatibility complex (MHC) in both diseases. Polymorphisms of multiple classic and non-classic HLA genes within the HLA region displayed significant associations with each of the diseases. These observations suggest that some non-classic HLA gene variants also may contribute to susceptibility to or protection from these two diseases. However, because of the extensive linkage disequilibrium (LD) between genes within the HLA region, some of observed disease associations may be due to LD. Alternatively, multiple true MHC associations may additively heighten or lower disease risk. To circumvent this problem, we propose herein to examine these candidate genes identified from the GWAS with deep sequencing in three distinct ethnic groups. Sequencing candidate genes will provide the highest resolution for viewing genetic polymorphisms that can be used to construct comprehensive haplotype combinations, as well as to identify rare alleles. Subsequently, identified haplotypes and rare alleles will be examined in different ethnic groups for confirmation in an effort to locate causative gene variants to the diseases. The overall long-term objective of this proposal is to define the roles of specific HLA-region gene variations in susceptibility to or protection from SSc and AS, as well as in association with specific clinical presentations, disease subgroups and/ or severity. Information obtained from these studies will ultimately lead to understanding of disease pathogenesis and development of target specific therapies in SSc and AS. This proposal will fulfill the mission of the FOA to study HLA region genomics in immune-mediated diseases.
(provided by applicant): The greatest risk for immune-mediated diseases such as systemic sclerosis (SSc) and ankylosing spondylitis (AS) have been associated with specific gene variants within the major histocompatibility complex. Our proposal aims to define these variants that contribute to greater or lower susceptibility to SSc and AS, which will ultimately lead to understanding of disease pathogenesis and development of target specific therapies.
|Guo, Shicheng; Li, Yuan; Wang, Yi et al. (2016) Copy Number Variation of HLA-DQA1 and APOBEC3A/3B Contribute to the Susceptibility of Systemic Sclerosis in the Chinese Han Population. J Rheumatol 43:880-6|
|Liu, Jing; Dong, Zheng; Zhu, Qi et al. (2016) TNF-Î± Promoter Polymorphisms Predict the Response to Etanercept More Powerfully than that to Infliximab/Adalimumab in Spondyloarthritis. Sci Rep 6:32202|
|Liu, Qingmei; Chu, Haiyan; Ma, Yanyun et al. (2016) Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-Î² Signaling Pathway. Sci Rep 6:27610|
|Wei, Peng; Yang, Yang; Guo, Xinjian et al. (2016) Identification of an Association of TNFAIP3 Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis-Associated Genetic and Environmental Factors. Arthritis Rheumatol 68:749-60|
|Cortes, A; Maksymowych, W P; Wordsworth, B P et al. (2015) Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann Rheum Dis 74:1387-93|
|Salazar, Gloria A; Assassi, Shervin; Wigley, Fredrick et al. (2015) Antinuclear antibody-negative systemic sclerosis. Semin Arthritis Rheum 44:680-6|
|Chu, Haiyan; Wu, Ting; Wu, Wenyu et al. (2015) Involvement of collagen-binding heat shock protein 47 in scleroderma-associated fibrosis. Protein Cell 6:589-98|
|Mayes, Maureen D; Bossini-Castillo, Lara; Gorlova, Olga et al. (2014) Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am J Hum Genet 94:47-61|
|Wu, Ting; Chu, Haiyan; Tu, Wenzhen et al. (2014) Dissection of the mechanism of traditional Chinese medical prescription-Yiqihuoxue formula as an effective anti-fibrotic treatment for systemic sclerosis. BMC Complement Altern Med 14:224|
|Wang, Jiucun; Guo, Xinjian; Yi, Lin et al. (2014) Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population. PLoS One 9:e87363|
Showing the most recent 10 out of 37 publications