FokI polymorphism at translation initiation site of the vitamin D receptorgene predicts bone mineral density and vertebral fractures in postmenopausal Italian women

A novel T/C polymorphism (ATG to ACG) at the translation initiation site of the vitamin D receptor (VDR) gene, defined by FokI restriction endonucleas e, has been recently associated with variation in bone mineral density (BMD ) and rates of bone loss in a group of postmenopausal Mexican-American wome n. The presence of the restriction site, designated as f, allows protein tr anslation to initiate from the first ATG, while the allele lacking the site , indicated as F, initiates translation at a second ATG. In this study, we investigated the role of FokI polymorphism in a group of 400 postmenopausal women of Italian descent stratified for BMD into osteoporotic (n = 164), o steopenic (n = 117), and normal (n = 119) groups;. There were 159 (41%) FF homozygotes, 55 (14%) ff homozygotes, and 186 (45%) Ff heterozygotes. In th e whole population, we observed a weak association between FokI polymorphis m and lumbar BMD (p = 0.06; analysis of covariance [ANCOVA]) but not with f emoral neck BMD (p = 0.5, ANCOVA). Interestingly, the effect of FokI genoty pes on lumbar BMD was influenced by the years since menopause such that dif ferences in BMD related to different VDR allelic variants were greater amon g women in the first 5 years of menopause (p = 0.04, ANCOVA), progressively declining afterward. In addition, a significantly higher prevalence of ff genotype in osteoporotic than in osteopenic and normal women was observed ( p = 0.04, Chi-square test). Finally, ff genotype resulted significantly ove r-represented in the group of women with a vertebral fracture as compared w ith controls (p = 0.003, Chi-square test), equivalent to a relative risk of 2.58 (95% confidence intervals 1.36-4.91). We conclude that in this popula tion, FokI polymorphism at the VDR gene locus accounts for a part of the he ritable component of BMD at the lumbar spine.