In order to understand the natural history and outcome of patients with AS, this proposal will study multiple ingredients in a model of disease outcome. Any true comprehension of this disease must consider genetic factors, disease activity over time, treatment with new biologic agents, and psychosocial constructs. Outcome is a complex construct as well, taking into account patient reported factors of pain and function loss, accumulated radiographic damage, and morbid events such as hip replacements, etc. Our previous experience in assessing this disease in a cross-sectional manner has led us to approach the question in a model that can quantify and examine each factor for its relative importance to the outcome variables. In order to accomplish this objective, we propose 5 Aims:1) we will recruit and retain 300 additional patients with AS of any disease duration to complement the 600 USA patients already recruited and to retain those already enrolled in the ongoing PSOAS cohort;2) we will perform an analysis of 675K SNPs as predictors of disease outcome in 1000 UK patients with AS in terms of functional impairment (as measured by the BASFI), disease activity (as measured by the BASDAI) and age at disease onset (disease duration). These 675K SNPs will be identified as predictors for disease susceptibility as part of a genome wide scan in 1000 UK AS patients as performed in project 1, aim 2;3) we will confirm and extend the observations from Aim 2 in a cohort of 1500 USA AS patients with SNPs derived from the output of Aim 2 in this proposal and from Project 1, Aim 2. In this aim we will identify SNPs that are predictive of functional and radiological outcomes in the large (900 patient) PSOAS cohort of AS patients from North America that either has already been or will be recruited and retained in Aim 1 of this project;4) we will identify and examine the relationships between psychosocial factors (coping, helplessness, and mood disturbances) and progression of disease in our newly identified cohort (300 subjects) as well as in follow-up intervals of the previously identified PSOAS cohort (400 subjects);5) we will examine the relative contributions of genetic and all of the other non-genetic factors (addressed in Aims 2-4 above) that contribute to outcome in this cohort using analytic techniques developed in Project 4 of this submission. It is anticipated that non-genetic components of disease outcome and progression (including treatments with biologic agents) will be able to be quantified and examined for their relative importance to patient outcome.
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