Program Project Grant - Genetics and Ankylosing Spondylitis (AS) Pathogenesis

描述(由申请人提供)：本次续签申请的研究主题是进一步表征强直性脊柱炎(AS)的遗传基础，因为它影响家庭成员的疾病易感性、严重性、表型外显性，以及这些与疾病相关的基因多态与动物模型和人类疾病的关系。这里提出的工作建立在上一轮资助的进展基础上，在上一轮资助中，对AS易感性的遗传基础进行了广泛的定义，建立了现存AS患者中最大且特征最佳的纵向疾病队列，并检查了遗传和非遗传因素对疾病严重性的影响，其中开发了一份问卷，已在美国普通人群中应用(NHANES 2009和2010)，并在现有的最高风险人群(一级)中验证了轴性脊柱炎(Spa)。 AS患者的亲属(FDR‘s)，并开发了新的范例来分析在疾病发病机制中起作用的遗传网络。在下一轮资助中，将确定实际的致病变异的特征，特别是那些未被Tag SNP研究(项目1)识别的变异，将确定这些突变和其他基因对结果的影响，特别是结构(即放射学)严重程度(项目2)，以及对更广泛的表型(轴向SpA-项目3)的发展以及AS患者的高风险组中相关共病的发展的影响，最后是TH17通路的表征，这些新的基因变体中的许多涉及到小鼠模型和人类SpA患者及其家庭成员的疾病易感性。这将导致了解这些疾病风险基因的功能后果(项目4)。这些项目将由行政和样本处理核心A和生物统计和管理核心B提供服务。我们一直在进行并最终提出的遗传和生物标记物特征可能允许在发病时对其进行表征，其中不仅将揭示疾病触发的重要线索，还将揭示潜在的治疗干预措施。

DESCRIPTION (provided by applicant): The research theme underlying this renewal application is the further characterization of the genetic basis of ankylosing spondylitis (AS), insofar as it affects disease susceptibility, severity, phenotype penetrance in family members and how these disease-related genetic polymorphisms relate to animal models and human disease. The work here proposed builds on the progress in the last cycle of funding where the genetic basis of susceptibility to AS was extensively defined, where the largest and best characterized longitudinal disease cohort of AS patients extant was established and examined for the impact of genetic and nongenetic factors on disease severity, where a questionnaire was developed that has been applied in the general U.S. population (NHANES 2009 and 2010) and validated for axial spondyloarthritis (SpA) in the highest risk population extant, the first degree relatives (FDR's) of AS patients, and where novel paradigms to analyze the genetic networks operative in disease pathogenesis were developed. In the next cycle of funding the actual disease-causing variants will be characterized, specifically those not identified by tag SNP studies (Project 1), the impact of these mutations and other genes on outcome, especially structural (i.e. radiographic) severity will be determined (Project 2), as well as on development of the broader phenotype (axial SpA-Project 3) and of associated co-morbidities in the group at highest risk- HLA-B27 positive risk-first degree relatives of AS patients, and finally the characterization of the TH17 pathway, implicated by many of these novel genetic variants in disease susceptibility in murine models and human SpA patients and their family members, which will result in understanding the functional consequences of these disease risk genes (Project 4).These Projects will be served by an Administrative and Sample Handling Core A and a Biostatistical and Management Core B. The genetic and biomarker characterizations we have been carrying out and further propose ultimately may allow characterization of this AS at onset, where not only important clues in disease triggering but also potential therapeutic interventions would be revealed.