Genetics and Ankylosing Spondylitis (AS) Pathogenesis

描述（由申请人提供）：本提案的目的是确定强直性脊柱炎（AS）易感性的遗传基础。与其他已经完成AS基因组扫描的研究组（牛津和巴黎，法国）一起，我们通过合并488个家系和589个受影响的同胞对（ASP）完成了荟萃分析，其中不仅确认了一些先前描述的染色体区域（在6p，6 q，10 q，16 q上），而且还出现了先前未注意到的新区域（在1 q，5 q上）。因此，该项目围绕四个假设：1）MHC对AS遗传基础的贡献，虽然主要由HLA-B27提供，但被其他MHC影响所增强，需要新的方法来阐明; 2）非MHC基因的贡献，虽然至关重要，但足够小，需要大样本量和包括不同种族群体的独立队列的确认; 3）这些遗传因素以复杂的方式相互作用，影响疾病的易感性; 4）严格和一致的表型特征对任何遗传研究的成功至关重要，特别是AS。因此，本项目的具体目标是：1）通过使用基于家族的研究和病例对照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;通过在实施一致的诊断标准（具有可用放射照片的改良纽约标准）的较大家系集合中进行基因组扫描来验证荟萃分析所涉及的AS易感区域; 3.通过检查北美AS家族和不相关病例和对照中这些基因的SNP和单倍型，在来自相同种族背景的英国AS家族中以及进一步在中国和墨西哥家族中确认，来检查在我们的全基因组扫描中鉴定的区域中的40个潜在候选基因; 4.研究特定目标3中鉴定的候选区域/基因与其他与AS风险相关的MHC和非MHC基因的相互作用。

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.