Although HLA-B27 is regarded as an essential feature for the development of ankylosing spondylitis (AS, recent studies have implicated other genes and chromosomal regions, both inside and outside the major histocompatibility complex (MHC), in the pathogenesis of the disorder. The entire MHC contribution has been calculated at only 31 percent. Linkage analysis of sib pairs from the United Kingdom has shown eight chromosomal regions, including the MHC, to have moderate evidence of linkage to AS. However, many genes are contained in these regions, and which are the actual disease susceptibility genes within these regions has not been established. Thus, the specific aims of this proposal are: 1) to establish a consortium of investigators with a recent record of clinical or genetic research in AS (and hence established patient cohorts) based at 10 academic medical centers throughout North America (the North American Spondylitis Consortium-NASC) in order to identify from their cohorts families with at least two siblings fulfilling the modified New York criteria for AS; 2) from the membership of the Spondylitis Association of America (SAA), to identify similarly affected families and verify the diagnoses in both groups by questionnaire, medical record review and pelvic radiographs; 3) to collect 50 ml of blood from affected and unaffected sib pairs and, when available, both their parents in order to establish a bank of sera, genomic DNA and frozen lymphocytes from these 400 families; 4) to characterize the MHC contribution to predisposition to AS by DNA typing for HLA-B27 alleles, B60 and HLA-DRB1, DQA1 and DQB1 alleles; 5) to conduct a genome wide search using closely spaced microsatellite markers in sib pairs concordant and discordant for AS in the 400 Caucasian families; 6) to conduct microsatellite polymorphism analyses of non-MHC genes using multipoint analyses for fine mapping studies of genes linked to AS using transmission disequilibrium testing (TDT); and finally, 7) to study sequence variation of three to four candidate genes in 25 AS patients and 25 controls to identify the mutations an disease-relevant polymorphisms involved in AS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046208-03
Application #
6375237
Study Section
Special Emphasis Panel (ZAR1-BHD-B (M2))
Program Officer
Serrate-Sztein, Susana
Project Start
1999-09-10
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$984,253
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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
Reveille, John D (2014) An update on the contribution of the MHC to AS susceptibility. Clin Rheumatol 33:749-57
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
Joshi, Reeti; Reveille, John D; Brown, Matthew A et al. (2012) Is there a higher genetic load of susceptibility loci in familial ankylosing spondylitis? Arthritis Care Res (Hoboken) 64:780-4
Davidson, Stuart I; Liu, Yu; Danoy, Patrick A et al. (2011) Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese. Ann Rheum Dis 70:289-92
Evans, David M; Spencer, Chris C A; Pointon, Jennifer J et al. (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761-7
Danoy, Patrick; Pryce, Karena; Hadler, Johanna et al. (2010) Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease. PLoS Genet 6:e1001195
Tsui, Florence W L; Haroon, Nigil; Reveille, John D et al. (2010) Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann Rheum Dis 69:733-6
Australo-Anglo-American Spondyloarthritis Consortium (TASC); Reveille, John D; Sims, Anne-Marie et al. (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123-7
Sims, A-M; Timms, A E; Bruges-Armas, J et al. (2008) Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis 67:1305-9

Showing the most recent 10 out of 22 publications