GENETIC MUTATIONS AS ETIOLOGIC FACTORS IN OSTEOARTHRITIS

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DESCRIPTION: (Verbatim) - The etiology of osteoarthritis (OA) is at present unknown. Genetic, environmental, metabolic, and biomechanical factors have been suggested as playing possible roles. Interest in a genetic role for the etiology of OA has expanded based on clinical identification of positive inheritance patterns in certain disease subsets such as Heberden's nodes, differences in the prevalence of OA among different races and populations, and the demonstration of type II collagen gene (COL2A1) mutations as a cause of primary generalized OA. Evidence suggests mutations in loci other than COL2A1 may be important in familial OA as well. Our studies have demonstrated multiple loci of COL2A1 mutations (Arg519-Cys, Arg75-Cys) associated with familial OA and, based on founder studies, identified susceptibility sites ("hot-spots") of mutation. In addition, our serum marker studies have demonstrated an imbalance between matrix degradation and synthesis in mutation-positive, OA-positive individuals. The studies proposed in our further series of investigations will: Aim 1) locate and identify collagen and/or non-collagen matrix-associated genes which are associated with primary OA utilizing the over 35 families already available; investigational approaches include candidate gene screening; high-throughput linkage analysis of the human genome using highly polymorphic markers; and analysis of complex traits using data derived from genome screening in combination with computerized modeling and simulation methods; and Aim 2) expand our study of serum markers to further define pathophysiologic mechanisms and clinical utility in OA utilizing new multiple large kindreds now available. Studies based on individuals with genetic mutations destined to develop OA at a defined age (2nd to 3rd decades) allow a unique, otherwise unavailable opportunity for correlative marker assessments. The overall proposal will further insights into genetically related OA, and pathophysiologic mechanisms.