Polymorphisms of the vitamin D receptor gene (VDR) have been shown to be
associated with several complex diseases, including osteoporosis, but the
mechanisms are unknown and study results have been inconsistent. We
therefore determined sequence variation across the major relevant parts of
VDR, including construction of linkage disequilibrium blocks and
identification of haplotype alleles. We analyzed 15 haplotype-tagging SNPs
in relation to 937 clinical fractures recorded in 6,148 elderly whites
over a follow-up period of 7.4 years. Haplotype alleles of the 5' 1a/1e,
1b promoter region and of the 3' untranslated region (UTR) were strongly
associated with increased fracture risk. For the 16% of subjects who had
risk genotypes at both regions, their risk increased 48% for clinical
fractures (P = .0002), independent of age, sex, height, weight, and bone
mineral density. The population-attributable risk varied between 1% an
