The association of ankylosing spondylitis (AS) with a gene of the Major Histocompatibility Complex (MHC), HLA-B27, has emerged as one of the best examples of disease association with a hereditary marker. However, the relative frequency of this marker in Caucasians (6-8%) far exceeds that of AS(0.2%). Also, B27-positive relatives of AS patients are far more likely(up to 29%) to have AS than B27 positive relatives of controls(1-2%). The most likely explanation for these apparent discrepancies is (an) additional gene(s) whose product(s) interact with B27 to predispose to AS. Having identified by restriction fragment length polymorphism (RFLP) analysis a 9.2kb Pvu II RFLP that further distinguishes B27 positive AS patients from B27 positive controls and which, although MHC-related, segregates independently of B27 haplotypes in multiplex AS family studies, the investigators here propose to further characterize at the molecular level this """"""""second AS gene"""""""". First, the 9.2kb RFLP will be cloned from a B27-positive AS patient into EMBL 3, and a restriction map thereof determined. Sub-fragments will then be sought that, on rehybridization, are specific for the 9.2kb RFLP. The new probe thus generated will be utilized to screen a cosmid genomic library from an AS patient with the 9.2kb fragment, to look for cosmid clones containing the AS-associated RFLP in order that new probes might be generated from overlapping or adjacent DNA sequences that might be more disease-specific. DNA fragments found to be most specific for AS will then be sequenced and compared with the sequences of other MHC-associated genes. Alternatively, the new 9.2kb-specific probe (or any other new more disease-specific probe generated in this study) will be utilized to map the fragment relative to other MHC-associated genes by pulse gradient gel electrophoresis. The identification and characterization of this """"""""second AS gene"""""""" would not only allow subsequent analyses evaluating the product of this gene, but also give important clues as to the very genetic predisposition to AS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AR039325-01
Application #
3457011
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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