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.