Our prior work established the foundation for discovering novel insights into the genetic susceptibility and severity of ankylosing spondylitis (AS) as well as genetic-associated mechanistic pathways driving outcomes in this disease. During the renewal of Project 2, we will: 1) expand those insights by combining with another North American cohort of similar size (from Toronto and Edmonton, Canada) that we have already genotyped and followed with almost identical measures (Aim 1);2) assess and improve cun-ent radiographic scoring systems and determine the characteristics of radiographic progression (Aim 2);and 3) examine a critical association between cardiovascular outcomes and premature mortality in AS while concurrently exploring a relationship between chronic gut inflammation, cardiac morbidity, and AS outcome and mortality (Aim 3). The rationale for Aim 1 comes from the need to examine a robust spectrum of disease phenotype from the very early years of AS through later stage disease. This combined cohort is critical to the analyses of radiographic progression, cardiovascular risk, and gut inflammation addressed in Aims 2 and 3. The rationale for Aim 2 is that the most widely used radiographic scoring system - the modified Stokes Ankylosing Spondylitis Spinal Score (mSASSS), a scoring system that includes measures of erosions, sclerosis, squaring, syndesmophytes, and ankylosis - has several theoretical and methodological limitations for measuring bone formation and disease progression. The rationale for Aim 3 comes from emerging data that the frequency of HLA-B27 in adults from 20-69 years of age declines with increasing age and that unchecked inflammation, presumably from gut ongin, may be responsible for the premature cardiovascular morbidity and mortality that occurs in AS patients relative to the general population. The ability to address these issues during the renewal of Project 2 will allow us to significantly contribute to the understanding of disease initiation, progression, and outcomes in AS.
AS patients have a large variation in outcomes;some patients fuse their spine completely while others do not. Many have premature heart disease and in some cases, early death. Our studies are designed to discover the genetic as well as the environmental predictors of these individual outcomes.
|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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