Genetics and Ankylosing Spondylitis (AS) Pathogenesis

描述（由申请人提供）：本提案的目的是定义强直性脊柱炎（AS）易感性的遗传基础。与其他已经完成AS基因组扫描的研究小组（牛津和法国巴黎）一起，我们完成了一项荟萃分析，将488个谱系和589对受影响的兄弟姐妹（asp）结合起来，不仅证实了一些先前描述的染色体区域（6p, 6q, 10q, 16q），而且还发现了以前未注意到的新区域（1q, 5q）。因此，这个项目围绕着四个假设；1) MHC对AS遗传基础的贡献，虽然主要由HLA-B27提供，但也受到其他MHC影响的增强，这需要新的方法来阐明；2)非mhc基因的贡献虽然至关重要，但却很小，需要大样本量并在包括不同种族群体在内的独立队列中进行确认；3)这些遗传因素以复杂的方式相互作用，影响疾病易感性；4)严格和一致的表型特征对任何遗传研究的成功都至关重要，尤其是对AS的研究。因此，该项目的具体目标是：1)通过使用基于家族和病例对照的研究，以及通过检查跨越相关HLA基因的单倍型块，来表征MHC对AS易感性的贡献；2. 为了验证meta分析所涉及的AS易感区域，通过在更大的谱系集合中进行基因组扫描，其中执行一致的诊断标准（修改的纽约标准和可用的x线片）；3. 通过检查北美AS家族和来自相同种族背景的英国AS家庭以及中国和墨西哥家庭中确认的不相关病例和对照中这些基因的SNP和单倍型，在我们的全基因组扫描中确定的区域中检测40个潜在的候选基因；4. 研究特异性靶3中鉴定的候选区域/基因与其他MHC和非MHC基因与AS风险的相互作用。

DESCRIPTION (provided by applicant): The goal of this proposal is to define the genetic basis of ankylosing spondylitis (AS) susceptibility. Together with the other groups (Oxford and Paris, France), who also have completed genome scans of AS, we have completed a meta-analysis by combining 488 pedigrees and 589 affected sib pairs (ASPs), where not only were some previously described chromosomal regions confirmed (on 6p, 6q, 10q, 16q) but also new regions emerged not noted previously (on 1q, 5q). Thus, this project is centered around four hypotheses; 1) that the MHC contribution to the genetic basis of AS, though primarily provided by HLA-B27, is augmented by other MHC influences that require novel approaches to elucidate; 2) that the contribution of non-MHC genes, though vital, is sufficiently small to require large sample sizes and confirmation in independent cohorts including different ethnic groups; 3) that these genetic factors interact with each other in a complex manner to influence disease susceptibility; and 4) that rigid and consistent phenotypic characterization is crucial to the success of any genetic study, particularly that of AS. The specific aims of this project are, therefore: 1) To characterize the MHC contribution to AS susceptibility by using both family based and case-control studies and by examining haplotype blocks spanning the relevant HLA genes; 2. To validate the AS susceptibility regions implicated by the meta-analysis by conducting a genome-scan in a larger collection of pedigrees where consistent criteria of diagnosis (modified New York Criteria with available radiographs) are enforced; 3. To examine 40 potential candidate genes in regions identified in our genomewide scans by examining SNP's and haplotypes of these genes in North American AS families and in unrelated cases and controls, confirmed in British AS families from the same ethnic background and further in Chinese and Mexican families; 4. To investigate interaction of candidate regions/genes identified in Specific Aim 3 with other MHC and non MHC genes implicated in the risk for AS.