The goal of this proposal is to define the genetic basis of ankylosing spondylitis (AS) susceptibility. Together with the other groups (Oxford and Paris, France), who also have completed genome scans of AS, we have completed a meta-analysis by combining 488 pedigrees and 589 affected sib pairs (ASPs), where not only were some previously described chromosomal regions confirmed (on 6p, 6q, 10q, 16q) but also new regions emerged not noted previously (on 1q, 5q). Thus, this project is centered around four hypotheses; 1) that the MHC contribution to the genetic basis of AS, though primarily provided by HLA-B27, is augmented by other MHC influences that require novel approaches to elucidate; 2) that the contribution of non-MHC genes, though vital, is sufficiently small to require large sample sizes and confirmation in independent cohorts including different ethnic groups; 3) that these genetic factors interact with each other in a complex manner to influence disease susceptibility; and 4) that rigid and consistent phenotypic characterization is crucial to the success of any genetic study, particularly that of AS.
The specific aims of this project are, therefore: 1) To characterize the MHC contribution to AS susceptibility by using both family based and case-control studies and by examining haplotype blocks spanning the relevant HLA genes; 2. To validate the AS susceptibility regions implicated by the meta-analysis by conducting a genome-scan in a larger collection of pedigrees where consistent criteria of diagnosis (modified New York Criteria with available radiographs) are enforced; 3. To examine 40 potential candidate genes in regions identified in our genomewide scans by examining SNP's and haplotypes of these genes in North American AS families and in unrelated cases and controls, confirmed in British AS families from the same ethnic background and further in Chinese and Mexican families; 4. To investigate interaction of candidate regions/genes identified in Specific Aim 3 with other MHC and non MHC genes implicated in the risk for AS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
1P01AR052915-01A1
Application #
7168285
Study Section
Special Emphasis Panel (ZAR1-YZW-K (M1))
Program Officer
Serrate-Sztein, Susana
Project Start
2006-08-01
Project End
2011-06-30
Budget Start
2006-08-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$1,555,604
Indirect Cost
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
Lee, MinJae; Rahbar, Mohammad H; Brown, Matthew et al. (2018) A multiple imputation method based on weighted quantile regression models for longitudinal censored biomarker data with missing values at early visits. BMC Med Res Methodol 18:8
Dau, Jonathan D; Lee, MinJae; Ward, Michael M et al. (2018) Opioid Analgesic Use in Patients with Ankylosing Spondylitis: An Analysis of the Prospective Study of Outcomes in an Ankylosing Spondylitis Cohort. J Rheumatol 45:188-194
Rahbar, Mohammad H; Lee, MinJae; Hessabi, Manouchehr et al. (2018) Harmonization, data management, and statistical issues related to prospective multicenter studies in Ankylosing spondylitis (AS): Experience from the Prospective Study Of Ankylosing Spondylitis (PSOAS) cohort. Contemp Clin Trials Commun 11:127-135
Jamalyaria, Farokh; Ward, Michael M; Assassi, Shervin et al. (2017) Ethnicity and disease severity in ankylosing spondylitis a cross-sectional analysis of three ethnic groups. Clin Rheumatol 36:2359-2364
Kehl, Amy S; Learch, Thomas J; Li, Dalin et al. (2017) Relationship between the gut and the spine: a pilot study of first-degree relatives of patients with ankylosing spondylitis. RMD Open 3:e000437
Kehl, Amy S; Corr, Maripat; Weisman, Michael H (2016) Review: Enthesitis: New Insights Into Pathogenesis, Diagnostic Modalities, and Treatment. Arthritis Rheumatol 68:312-22
Robinson, Philip C; Claushuis, Theodora A M; Cortes, Adrian et al. (2015) Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol 67:140-51
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
Kiltz, U; van der Heijde, D; Boonen, A et al. (2015) Development of a health index in patients with ankylosing spondylitis (ASAS HI): final result of a global initiative based on the ICF guided by ASAS. Ann Rheum Dis 74:830-5
Cortes, Adrian; Pulit, Sara L; Leo, Paul J et al. (2015) Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun 6:7146

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