Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density.

UNLABELLED

Possible contribution of vitamin D-binding protein (DBP) gene for determination of BMD was tested by characterizing 13 SNPs in 384 adult Japanese women. When the effect of a specific single SNP was tested, five SNPs (-39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) correlated with BMD significantly at various levels. The chromosomal dosage of one haplotype (T-C-C-G-T-C in -39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E, and IVS11+1097G>C) displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Multiple regression analyses revealed a most significant correlation with the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis.

INTRODUCTION

Osteoporosis results from the interplay of multiple environmental and genetic determinants. The gene encoding vitamin D-binding protein (DBP), a key factor for regulating calcium homeostasis through the vitamin D endocrine system, is a probable candidate for conferring susceptibility to osteoporosis.

METHODS

To test a possible contribution of the DBP gene for determination of bone mineral density (BMD) of adult women, we have characterized 13 single nucleotide polymorphisms (SNPs) within the DBP gene in DNA from 384 adult Japanese women and attempted to correlate specific SNPs with BMD.

RESULTS AND CONCLUSIONS

Sixteen major haplotypes accounted for 80% of the variations, indicating allelic complexity in this genomic region. Pairwise linkage disequilibrium (LD), measured by the D' and r2 statistics, demonstrated a general pattern of decline with increasing distance, but individual LD values within small genomic segments were diverse. Regression analysis for adjusted BMD revealed significant correlation with respect to five of them (-39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) at various levels. An intronic SNP (IVS11+1097G>C) with the highest significance of association (p = 0.006) showed significant LD with four SNPs located around the first exon (r2 values > 0.18, D' > 0.5). A non-synonymous coding SNP, D432E, showed a comparable level of correlation, but it was in a moderate LD only with IVS11+1097G>C. The chromosomal dosage of one haplotype (T-C-C-G-T-C in -39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E and IVS11+1097G>C) estimated in each subject displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Furthermore, multiple regression analyses revealed that the most significant correlation was achieved for the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis.