Genetics and Ankylosing Spondylitis (AS) Pathogenesis

描述(由申请人提供)：本提案的目标是确定强直性脊柱炎(AS)易感性的遗传基础。与已经完成AS基因组扫描的其他小组(牛津和法国巴黎)一起，我们通过结合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(位于6p、6q、10q、16q)，而且出现了以前没有注意到的新区域(在1q、5q)。因此，该项目围绕四个假设展开：1)MHC对AS遗传基础的贡献，虽然主要由人类白细胞抗原-B27提供，但被其他MHC影响所扩大，需要新的方法来阐明；2)非MHC基因的贡献虽然重要，但足够小，需要大样本和包括不同种族在内的独立队列中的确认；3)这些遗传因素以复杂的方式相互作用，影响疾病易感性；以及4)严格和一致的表型特征对任何遗传学研究的成功，特别是AS的成功至关重要。因此，该项目的具体目标是：1)通过使用基于家庭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；2.通过对执行一致的诊断标准的更大的家系集合进行基因组扫描来验证Meta分析所涉及的AS易感区域(修改后的纽约标准和可用的X线片)；3.在全基因组扫描中确定的40个候选基因中检测这些基因的SNP和单倍型，这些基因在北美AS家系和无关病例和对照中，在英国确诊为具有相同种族背景的AS家系，并进一步在中国和墨西哥家系中被确认；4.研究特定目标3中确定的候选区域/基因与其他MHC和非MHC基因之间的相互作用。

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.