Genetic and Molecular Basis of Joint Diseases
Many complex rheumatic joint diseases such as ankylosing spondylitis (AS) have a strong genetic component. AS is strongly associated with HLA-B27, but analyses of recurrence risk among family members suggest that at least three other genetic loci in addition to HLA-B27 are required to confer full susceptibility to AS. Despite several large genome-wide linkage studies on AS families, no clear non-MHC susceptibility loci has emerged. The difficulty in identifying non-MHC susceptibility genes in AS has suggested that AS patients comprise a heterogeneous population. Thus far, the use of candidate genes approach revealed that IL1 is a significant non-MHC susceptibility locus. We hypothesize that the variable genetic determinants among AS patients may perturb different aspects of a few biochemical pathways to yield a common pathologic outcome characterized by aberrant ossification at sites of chronic inflammation. Our approach has been to test specific candidate genes relating to certain pathways and to analyze the data separately in different gender and types of multiplex families. We initially focused on proteins such as ANK/ANKH [a regulator of inorganic pyrophosphate (PPi) transport] and TNAP (Tissue Non-specific Alkaline Phosphatase) which play important roles in PPi and Pi (inorganic phosphate) metabolism. Identification of precise biochemical and genetic features which are associated with AS will allow a correspondingly better classification of patients and thus lead to more accurate prognoses and more appropriate therapy.
Other ongoing projects include the study of 1. the functional consequences of known ANKH mutations in familial calcium pyrophosphate dihydrate crystal deposition disease (CPPDD); 2. ank/ank mouse as a model for chronic human joint diseases; and 3. the interplay of proteins with significant roles in PPi and Pi metabolism and its relevance to bone/joint biology.
1. TSUI FWL, Tsui HW, Cheng EY, Stone M, Payne U, Reveille J, Shulman MJ, Paterson AD, Inman RD. 2003 Arthritis Rheum 48:791-797.
2. Tsui HW, Siminovitch KA, De Souza L, TSUI FWL. 1993 Nature Genet. 4:124-129.
3. Cayabyab FS, TSUI FWL, Schlichter LC. 2002 J Biol Chem 277:48130-48138.
4. Smith GAM, Tsui HW, Newell E, Jiang Z, Zhu X-P, TSUI FWL, Schlichter LC. 2002 J Biol Chem 277:18528-18534.
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