HEREDITY IN OSTEOARTHRITIS--FARMINGTON OFFSPRING

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In recent years, a substantial genetic component has been recognized for many common rheumatic diseases, including ankylosing spondylitis, rheumatoid arthritis and gout. Several families with severe and progressive osteoarthritis at an early age and with associated genetic abnormalities have been found suggesting that osteoarthritis may also be due to inherited abnormalities. Nonetheless, these families are unusual and it is unclear whether osteoarthritis in the population at large is frequently due to genetic abnormalities and, if so, what the pattern of genetic inheritance is. In fact, there is astonishingly little information about the genetics of osteoarthritis in populations. No epidemiologic studies of the heritability of osteoarthritis have ever been performed in North America. The objective of this project is to examine the heritable nature of generalized osteoarthritis by looking at the association of generalized disease in the Framingham cohort and their offspring in the Framingham offspring group. To accomplish this objective, we will study OA of the hands and knees in members of the Framingham offspring group who had both parents in the cohort previously assessed for OA. In order to accomplish these objectives, we will pursue several specific aims: 1) we will characterize generalized OA and known risk factors for it in the targeted offspring; 2) we will read previously obtained hand x-rays from targeted cohort subjects for OA and characterize generalized OA in cohort subjects; 3) using complex segregation analysis and adjusting for the likelihood of osteoarthritis by taking into account age, sex, and other risk factors, we will evaluate whether generalized OA segregates in families and assess whether the pattern of inheritance best fits a single major gene model (dominant, codominant, recessive), a multifactorial model, a mixed model (a single gene effect in multifactorial background) or does not aggregate in families; and 4) we will identify families in which there is evidence of genetic, transmission for OA and perform a series of studies comparing disease expression in families with genetic transmission to those without it. In this analysis we will characterize genetic OA by its joint involvement and severity and will evaluate whether genetically transmitted OA is likely to be associated with certain specific risk factors. The identification of families with OA will facilitate future linkage in studies and molecular genetic studies which can focus on inherited defects.