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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
3P01AR052915-08S1
Application #
8926515
Study Section
Special Emphasis Panel (ZAR1-HL (M1))
Program Officer
Wang, Yan Z
Project Start
2005-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
$122,661
Indirect Cost
$43,011
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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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
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