Genetics and Ankylosing Spondylitis (AS) Pathogenesis

遗传学和强直性脊柱炎 (AS) 发病机制

• 批准号: 7267800
• 负责人: JOHN Duffin REVEILLE
• 金额: $ 150.53万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267800
• 关键词: Genetics; Ankylosing; Spondylitis; Pathogenesis

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.

描述（由申请人提供）：该提案的目标是确定强直性脊柱炎（AS）易感性的遗传基础。与其他小组（牛津和法国巴黎）一起，他们也完成了 AS 基因组扫描，我们通过结合 488 个家系和 589 个受影响的同胞对 (ASP) 完成了一项荟萃分析，其中不仅有一些先前描述的染色体已确认的区域（在 6p、6q、10q、16q），但也出现了之前未注意到的新区域（在 1q、5q）。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，但会受到其他 MHC 影响的增强，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，需要大样本量并在包括不同种族群体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，影响疾病的易感性； 4) 严格且一致的表型表征对于任何遗传学研究的成功至关重要，尤其是 AS 的成功。因此，该项目的具体目标是： 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. 通过在更大的家谱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，其中执行一致的诊断标准（使用可用射线照片修改纽约标准）； 3. 通过检查北美 AS 家族以及无关病例和对照中这些基因的 SNP 和单倍型，检查我们全基因组扫描中确定的区域中的 40 个潜在候选基因，这些基因在来自相同种族背景的英国 AS 家族中得到证实，并在中国和中国进一步得到证实。墨西哥家庭； 4. 研究特定目标 3 中确定的候选区域/基因与涉及 AS 风险的其他 MHC 和非 MHC 基因的相互作用。