Ankylosing spondylitis (AS),the most common defined subgroup of diseases known as spondyloarthritis? (SpA), includes a spectrum of disease characterized by a seronegative axial and/or peripheral arthritis with? familial clustering, overlapping mucocutaneous and visceral features, and associations with genes in the? major histocompatibility complex (MHC), including HLA-B27. Many seemingly distinct but inter-related? diseases in this group include AS, acute anterior uveitis (AAU), inflammatory bowel disease (IBD) and? psoriatic arthritis (PsA), reactive arthritis (ReA), and undifferentiated spondyloarthritis (uSpA). A large? number of studies have defined familial aggregation in AS and other SpA, however the findings are often? contradictory and lacking in any consistent genetic predisposing factors, due in part to biases in clinical? ascertainment or to power concerns due to small numbers of patients or pedigrees. There is a recent? growing trend to consider that SpA per se may be caused by specific genetic factors with which other genes? interact to cause the development of specific phenotypes (i.e. uveitis, IBD or psoriasis). Defining these? factors would be valuable in not only in providing clues to the pathogenesis of SpA itself and in specific? manifestations thereof, but also in designing generic or specific interventions that could reduce the? morbidities associated with these manifestations. In this project, we hypothesize that there are specific? genes that predispose to SpA, with which other genes interact to produce specific phenotypic manifestations? (i.e. psoriasis, uveitis, IBD, etc). In order to test this hypothesis, we will (1) define the prevalence and? patterns of well-defined phenotype expression of spondyloarthritis in the first degree relatives (FDRs) of? patients with AS, and (2) Aim 2: define the specific genetic architecture of the heterogeneity of SpA? phenotypes in the FDR of probands with AS by traditional genetic analysis methods and novel designs using? systems biology approach as defined in Project 4. Dr John Davis will serve as the Principal Investigator on? this project and Dr. Michael Weismans will serve as a Co-Principal Investigator. Drs. Davis and Weisman? have expertise in the area of clinical research and clinical care in patients with SpA. In addition, we will? collaborate with investigators on Projects 1 (Dr. Reveille), 2 (Dr. Weisman and Ward), and 4 (Drs. Lin and? Xiong). Drs. Lin and Xiong have expertise in both the genetic analyses and statistical modeling to be? performed. Study coordination will be performed by two coordinators. At UCSF, Stephanie Morgan will? coordinate 75% of the project administrative support. In addition, a coordinator at Cedar Sinai Medical? Center will provide 25% effort to the study. We will also have the help of Myriam Bianco at the Spondylitis? Association of America for patient recruitment and data collection.
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