Objective. To determine whether a polymorphism of the vitamin D receptor O R ) gene, already associated with osteoporosis, might also relate to the risk of osteoarthritis (OA).Methods. A population cohort of 351 postmenopausal women (ages 45-64 years) was studied using anteroposterior radiographs of the knee, which were graded for OA according to the Kellgren and Lawrence classification system. The VDR genotype was determined by using polymerase chain reaction and by digestion with the restriction enzyme Ta4 I.Results. The VDR allele "T" was associated with an increased risk of knee OA compared with the "t" allele, with an odds ratio of 2.82 (95% confidence interval 1.16-6.85; P = 0.02). A dominant pattern of risk was suggested. The frequency of the VDR genotype differed significantly between OA cases and controls (P = 0.03 by Fisher's exact test).Conclusion. A Tu4 I polymorphism of the VDR gene appears to be associated with an increased risk of knee OA. This is the first genetic locus that has been shown to influence the risk of early knee OA within the general population.Osteoarthritis (OA) is a common age-related and chronic skeletal condition that is associated with considerable morbidity and mortality, although at present the pathogenesis of this condition remains largely unknown. Many environmental factors and other independent conditions have been associated with OA, including obesity ( 1,2), previous injury and/or meniscectomy (3), knee-bending occupations (4), smoking (5,6), sex hormones and gynecologic disorders (6,7), and other metabolic factors (8,9). Family studies have suggested a strong genetic component to OA, with higher prevalence rates in first-degree relatives of index cases (10). A recent population-based UK study of twins has also demonstrated a clear genetic effect for radiologic OA of the knee and hand in women, with up to 65% of the variance being explained by genetic factors (11).OA of the knee and hip appears to be protective for osteoporotic fractures, with OA cases having a 5 1 0 % greater bone mass compared with controls (12). There is also evidence that OA is associated with underlying abnormalities in bone structure and mineralization, findings that are independent of body weight and skeletal loading (13). Since family and twin studies have demonstrated a strong genetic component to both OA (9,lO) and osteoporosis (14,15), we have hypothesized that common genetic factors may influence the development and/or protection against both conditions. We therefore have examined whether polymorphisms of the vitamin D receptor (VDR) gene, which were recently associated with low bone mineral density (BMD) in twin and population studies (15,16), were also associated with an altered risk of OA in a large population of normal, white women.
PATIENTS AND METHODSThe study design was a nested case-control study involving a population cohort of 1,003 women, who had a mean t SD age of 54.2 5 6.0 years. Women in the age range 45-64 years had been selected from a large (total of 11,000 registered patien...