Genetic epidemiology of osteoarthritis: Studies of familial aggregation and candidate genes

Abstract

O steoalthritis eO A) is the most common rheumatic disease and an i.mportant cause of disability in the elderly (l,2). It is characterized by a progressive degeneration of articular cartilage of diarthrodial joint::; without synovial inflammation or bone erosions. Il leads in a minority of subjects to clinical OA, Le. joint pain, limited range of motion of the affected jOint, joint effusion, local inflanul1atory reaction or crepitus. The dinical diagnosis of OA is confirmed by radiographic evidence, reflecting deterioration of cal1ilage with narrowing of joint space, formation of osteophytes at the joint margins, development of sclerosis of subchondral bone and development of pseudocystic areas in subchondral bone. OA is a chronic disease with a multifactorial etiology that includes genetic factors (e.g. skeletal disorders, heritable forms of obesity\\ other systemic factors (e.g. age, sex, race, bone mineral density), biomechanical factors (e.g. trauma, joint deformity, muscle weakness) and environmental factors (e.g. nutrition, spons, estrogen replacement therapy). The genetic influence on the etiology of OA has long been recognized for women with Heberden's nodes and for patients with generalized OA 0,4). There is growing evidence from POFulationbased studies, that comnlOn forms of OA, such as hand and knee OA, are also heritable (5-7). Various mutations in several genes have been detected in families with severe early-onset OA associated with heritable disorders as osteochondrodysplasia, Stickler syndrome, chondrocalcinosis or epiphyseal dysplasia (8,9). It remains largely unclear which genes are involved in causing common forms of OA that occur in an elderly population. Finally, genetic susceptibility to OA could also result from genetic influences on risk factors for OA, like obesity and increased bone mineral density. This thesis first describes some issues of consideration when studying the genetic epidemiology of a complex disease as osteoarthritis (Chapter 2.1). Next, the methods of the studies presented in this thesis are described