The association of bone mineral density with vitamin D receptor gene polymorphisms

A recent meta-analysis of 16 publications suggested that bone mineral densi ty (BMD) is not associated with vitamin D receptor (VDR) gene polymorphism (VDRGP) at the 0.05 significance level when a study with genotyping mistake s is excluded. We wished to determine whether 'positive' findings supportin g the BMD-VDRGP association may be explained by chance, and what factors af fect the outcomes of these studies. Seventy-five articles and abstracts on the association of VDRGP with BMD and related skeletal phenotypes published before January 1997 were identified. Twenty-three of 67 (34.3%) studies on spinal BMD and 22 of 51 (43.1%) on femoral neck BMD had found a BMD-VDRGP association at p < 0.05, significantly (p = 7 x 10(-14) for spinal BMD, p = 9 x 10(-16) for hip BMD) higher than the expected 5% false positive rate u nder the null hypothesis of 'no association'. 'Positive' results were more frequently observed in studies on females before the menopause than those o n females after the menopause (p < 0,02) or on male and female subjects com bined (p < 0.05) when skeletal phenotypes at any bone sites were considered . The 'positive rate' among studies was also influenced by the age range of subjects studied and by the inclusion of subjects with osteoporosis. It is concluded that: (1) BMD is associated with VDRGP with high levels of confi dence and (2) non-genetic factors and genetic heterogeneity interfere with the detection of the effects of VDRGP on bone phenotypes.