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.
This program project grant will further our understanding of the genetic contribution to not only what causes ankylosing spondylitis (AS), but also how genes influence the prognosis and complications of this disease. In addition, the spectrum of disease will be explored in family members of AS patients, and the impact of the products of these genes that are identified will be examined in animal models and in humans with AS.
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|Dau, Jonathan D; Lee, MinJae; Ward, Michael M et al. (2018) Opioid Analgesic Use in Patients with Ankylosing Spondylitis: An Analysis of the Prospective Study of Outcomes in an Ankylosing Spondylitis Cohort. J Rheumatol 45:188-194|
|Rahbar, Mohammad H; Lee, MinJae; Hessabi, Manouchehr et al. (2018) Harmonization, data management, and statistical issues related to prospective multicenter studies in Ankylosing spondylitis (AS): Experience from the Prospective Study Of Ankylosing Spondylitis (PSOAS) cohort. Contemp Clin Trials Commun 11:127-135|
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|Robinson, Philip C; Claushuis, Theodora A M; Cortes, Adrian et al. (2015) Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol 67:140-51|
|Cortes, A; Maksymowych, W P; Wordsworth, B P et al. (2015) Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann Rheum Dis 74:1387-93|
|Kiltz, U; van der Heijde, D; Boonen, A et al. (2015) Development of a health index in patients with ankylosing spondylitis (ASAS HI): final result of a global initiative based on the ICF guided by ASAS. Ann Rheum Dis 74:830-5|
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