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

描述（由申请人提供）：本次更新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，就其影响疾病易感性、严重程度、家族成员的表型多态性以及这些疾病相关的遗传多态性如何与动物模型和人类疾病相关而言。本文提出的工作建立在上一个资助周期的进展基础上，其中广泛定义了AS易感性的遗传基础，建立了现存AS患者的最大和最佳特征的纵向疾病队列，并检查了遗传和非遗传因素对疾病严重程度的影响，其中开发了一份调查问卷，已应用于美国普通人群（NHANES 2009和2010），并在现存最高风险人群（一级）中验证了中轴性脊柱关节炎（SpA） AS患者的亲属（FDR），并在那里开发了新的范式来分析在疾病发病机制中起作用的遗传网络。在下一轮的资助中，将对实际的致病变异进行表征，特别是那些没有通过标签SNP研究确定的变异。（项目1），这些突变和其他基因对结果的影响，特别是结构将确定（即影像学）严重度（项目2），以及更广泛的表型的发展（轴向SpA-Project 3）和AS患者的最高风险组- HLA-B27阳性风险-一级亲属中的相关共病，最后是TH 17通路的表征，在小鼠模型和人类SpA患者及其家庭成员中，许多这些新的遗传变异与疾病易感性有关，这将有助于理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品处理核心A和生物统计和管理核心B提供服务。我们一直在进行的遗传和生物标志物表征，并进一步提出最终可能允许在发病时表征这种AS，其中不仅揭示了疾病触发的重要线索，而且还揭示了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.