Genetic Architecture of Knee Radiographic Joint Space in Healthy Young Adults

Abstract

Evidence of a significant genetic component to the age-related degenerative joint disease osteoarthritis has been established, but the nature of genetic influences on normal joint morphology in healthy individuals remains unclear. Following up on our previous findings on the influence of body habitus on phenotypic variation in knee joint space [Duren et al., Human Biology 78:353-364 (2006)], the objective of the current study was to estimate the heritability of radiographic joint space in the knees of healthy young adults from a community-based sample of families. A sample of 253 subjects (mean age = 18.02 years) from 87 randomly ascertained nuclear and extended families was examined. Joint width (JW) and minimum joint space in the medial (MJS) and lateral (LJS) knee compartments were measured. A maximum-likelihood variance components method was used to estimate the heritability of MJS, LJS, and JW. Covariate effects of age, sex, age-by-sex interactions, stature, weight, and BMI were simultaneously estimated. Genetic correlation analyses were then conducted to examine relationships between trait pairs. MJS, LJS, and JW were each significantly heritable (p

KEY WORDS: KNEE JOINT SPACE, CARTILAGE, OSTEOARTHRITIS, HERITABILITY OF OSTEOARTHRITIS, X-RAY, FELS LONGITUDINAL STUDY.

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Idiopathic osteoarthritis (OA) is generally considered a disease of aging. Like many other aging conditions (e.g., osteoporosis), however, predisposition to OA can be recognized earlier in life, before overt degenerative changes become apparent in the joint, and may be oligogenic in nature. That is, the traits underlying the condition are influenced by a discrete set or sets of genes that together are responsible for variation in those traits. The genetic nature of predisposition to common complex diseases such as OA, however, has yet to be fully elucidated. In addition to their oligogenic nature, myriad potential epigenetic influences can significantly contribute, either individually or in combination, to variation in the expressed disease or disease traits. OA is particularly challenging for genetic epidemiologic study because of its multifactorial nature and the variation in the expression of subphenotypes that make up the disease (e.g., osteophytes, sclerosis, cysts, and joint space narrowing).

The first genetic study of OA was published by Stecher (1941), who noted that siblings of arthritic patients were more likely than unrelated individuals to demonstrate clinical signs of OA, particularly the presence of Heberden's nodes at the finger joints. More recent genetic studies have found that OA in many regions of the body is highly heritable (reviewed by Spector and MacGregor 2004). For example, twin studies have shown that hip, hand, and knee OA is 39-65% heritable (MacGregor et al. 2000; Spector et al. 1996). Heritability estimates for generalized OA and OA of the hand and spine based on sib-pair studies range from 56% to 78% (Bijkerk et al. 1999).

Recent evidence also suggests that two individual characteristic features of OA, osteophytes and joint space narrowing, may each have a unique genetic etiology. Both of these traits are heritable, but different genes that are associated with the two OA subphenotypes have been identified. The gene coding for COL2A1, a structural protein found in articular cartilage, has been shown to be associated with joint space narrowing in a population-based sample of older adults (Uitterlinden et al. 2000). In the same study sample the vitamin D receptor gene was identified as being involved in osteophytosis (Uitterlinden et al. 2000).

Genetic contributions to variation in articular cartilage thickness in particular are potentially the most important in terms of OA treatment and prevention. The nature of the genetic underpinnings of disease and nondisease states (i.e., normal healthy variation) is important for ultimately understanding complex traits and diseases. As researchers close in on specific genes involved in OA and look toward gene therapies for cartilage defects (Cucchiarini and Madry 2005; Evans et al. 2006), it is important that genetic influences on variation in normal healthy joint cartilage and adjacent bone also be considered. In a previous study we showed that body habitus has minimal influence on radiographie knee joint space (Duren et al. 2006). The objective of the current study is to estimate heritabilities of radiographie knee joint space and joint width and the genetic correlations between them in this same sample of healthy, young, skeletally mature individuals.

Subjects and Methods

Subjects. The study sample consisted of 253 individuals (132 men, 121 women) participating in the Fels Longitudinal Study. Initiated in 1929, the Pels Longitudinal Study is the world's largest and longest running study of human growth, development, and body composition change over the life span (Roche 1992). Pels Longitudinal Study participants are primarily white and live in or near southwest Ohio (Roche 1992). The 253 subjects in this particular study sample are from 87 nuclear and extended families. Among these 253 subjects there are 641 relative pairings represented, ranging from first-degree to sixth-degree relationships (Table 1).