Making Sense of Puzzling Genetic Association Studies: A Team Approach

Osteoporosis affects approximately 5 to 8 million Americans older than 50 years of age, and the lifetime risk for osteoporotic fracture is approximately 40% in white women and at least 13% in men (1, 2). Low bone mineral density (BMD) is the major clinical indicator of osteoporotic disease. However, the proportion of fractures attributable to osteoporosis by low BMD is modest, ranging from less than 10% to 44% for specific fracture types and only approximately 15% for all fractures (3). No single factor, such as BMD, can explain osteoporosis, which is a complex metabolic disease caused by actions and interactions among multiple genes, gene products, and environmental factors. These actions and interactions translate to loss of BMD, bone microarchitecture, and bone strength, as well as to nontraumatic fractures. Older women with a parental history of hip fracture have a 2-fold higher risk for hip fracture than those without such a history (4). Family and twin studies indicate that inherited characteristics are responsible for 50% to 80% of the phenotypic variation in traits related to low BMD and fracture (5).

The vitamin D receptor (VDR) gene has been a particular target of investigation. Vitamin D regulates bone formation and resorption, intestinal calcium absorption, calcium and phosphate homeostasis, and parathyroid hormone secretion. Vitamin D modulates expression of many genes by first interacting with VDR, which then forms complexes that bind to regulator gene regions. Allelic variations in VDR might affect the ability to bind vitamin D, which would disrupt vitamin D actions and consequently increase the risk for osteoporosis and fracture. More than 10 years ago, Morrison and colleagues (6) reported the association between VDR variants and BMD. This observation initiated …