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.
|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|
|Poddubnyy, Denis; Gensler, Lianne S (2014) Spontaneous, drug-induced, and drug-free remission in peripheral and axial spondyloarthritis. Best Pract Res Clin Rheumatol 28:807-18|
|Zhou, Xiaodong; Wang, Jiucun; Zou, Hejian et al. (2014) MICA, a gene contributing strong susceptibility to ankylosing spondylitis. Ann Rheum Dis 73:1552-7|
|Reveille, John D (2014) An update on the contribution of the MHC to AS susceptibility. Clin Rheumatol 33:749-57|
|Assassi, Shervin; Weisman, Michael H; Lee, MinJae et al. (2014) New population-based reference values for spinal mobility measures based on the 2009-2010 National Health and Nutrition Examination Survey. Arthritis Rheumatol 66:2628-37|
|Fatemi, Gita; Gensler, Lianne S; Learch, Thomas J et al. (2014) Spine fractures in ankylosing spondylitis: a case report and review of imaging as well as predisposing factors to falls and fractures. Semin Arthritis Rheum 44:20-4|
|Reveille, John D; Weisman, Michael H (2013) The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States. Am J Med Sci 345:431-6|
|International Genetics of Ankylosing Spondylitis Consortium (IGAS); Cortes, Adrian; Hadler, Johanna et al. (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45:730-8|
|Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2013) MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet 9:e1003336|
|Kaufman, Kenneth M; Zhao, Jian; Kelly, Jennifer A et al. (2013) Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann Rheum Dis 72:437-44|
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