Studies of HLA Region Genomics in Systemic Sclerosis and Ankylosing Spondyilitis

描述(申请人提供)：系统性硬化症(SSC)和强直性脊柱炎(AS)是两种免疫介导性疾病，前者是与人类白细胞抗原II类DR、DQ和DP等位基因相关的自身免疫性疾病，而后者是与人类白细胞抗原I类等位基因相关的自身炎症性疾病，最具特异性的是人类白细胞抗原B27。然而，MHC对这两种疾病的贡献都不能通过仅与这些经典的HL A等位基因的关联来完全解释。我们最近进行的全基因组关联研究表明，在这两种疾病中，最强的疾病关联基因位于主要组织相容性复合体(MHC)。多个经典和非经典的人类白细胞抗原基因在人类白细胞抗原区域内的多态与每一种疾病有显著的相关性。这些观察结果表明，一些非经典的人类白细胞抗原基因变异也可能有助于这两种疾病的易感性或保护性。然而，由于人类白细胞抗原区域内基因之间广泛的连锁不平衡(LD)，一些观察到的疾病关联可能是由于LD引起的。或者，多个真实的MHC关联可能会增加或降低疾病风险。为了绕过这个问题，我们在这里建议在三个不同的种族群体中用深度测序来检查这些从GWAs中识别的候选基因。对候选基因进行测序将为查看遗传多态提供最高分辨率，这些多态可用于构建全面的单倍型组合，以及识别稀有等位基因。随后，将在不同的种族群体中检查已识别的单倍型和稀有等位基因以进行确认，以努力定位导致这些疾病的基因变异。这项建议的总体长期目标是确定特定的HLA区域基因变异在SSC和AS的易感性或保护性中的作用，以及与特定的临床表现、疾病亚型和/或严重程度相关的作用。从这些研究中获得的信息最终将有助于了解疾病的发病机制，并开发针对SSc和AS的靶向特异性治疗方法。这项建议将完成FOA研究免疫介导性疾病中的人类白细胞抗原区域基因组学的使命。

DESCRIPTION (provided by applicant): 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.