Vitamin D receptor gene (VDR) polymorphisms: effect on bone mass, bone loss and parathyroid hormone regulation.

non-coding regions where frequent modifications On the basis of studies performed in families and and/or deletions of the base sequence are found and, twins, genetic influence can account for up to 80% of although this does not modify the resulting amino the variance in bone mineral density [1,2]. The final acids of the receptor structure, we know it can change bone mass is a result of all the mechanisms involved the transcription of the coding region or the stability in bone metabolism. In consequence, environmental of the mRNA. factors would have less effect on bone, and this would The changes in the sequence of bases in the coding depend on genetic conditioning. Taking into account region are less frequent, and they are usually located the effect of a great number of systemic and local in intronic portions (‘mute sequences’). On the other hormones on the regulation of bone metabolism, it is hand, the substitution of bases in the exon fragment highly possible to have a polygenic influence. In many does not always alter the resulting amino acid because studies, the influence of the genes encoding the vitamin we can obtain a synonym codon for the same amino D receptor (VDR) [3], the oestrogen receptor [4], the acid. There is only one modification described, in the synthesis of transforming growth factor (TGF)-b1 [5] second exon, which modifies the initial codon (ATG) or the synthesis of collagen type I a−1 [6 ] has been and whose presence adds three extra amino acids to shown. the vitamin D receptor structure. Although there are The VDR gene has been most widely studied among four sites at which base substitutions have been all these. The publication of the study of Morrison described, there is only one which can impose structural et al. [3] aroused great interest in the subject. Using changes on the amino acid sequence. Those mutations the BsmI restriction enzyme in a wide population of are related to changes in the non-coding region (known adult twins, they found variations of ±1 SD for the as the ‘linkage imbalance’ phenomenon) and can be mean values of bone mass among the three possible used as their indirect markers. genotypes. In their population-based study, they also The resulting new base sequences are recognized by found that the most favourable genotype passes the restriction enzymes which split the DNA at the site fracture threshold (−2 SD from the peak bone mass) where the mutation is located. If the restriction site is 10 years later than the less favourable genotype. present, we obtain a fragment of DNA containing the Although the molecular mechanism of action is not new sequence and type the allele using the lower case entirely clear, we know that the effect of vitamin D on initial letter of the restriction enzyme used. When the tissues is influenced by the type of metabolite as fragmentation does not occur, the allele is typed using well as by its levels, by the receptors’ density the upper case initial letter of the enzyme. So, taking (up-regulated by substratum levels) and probably also into account the chromosomic duplicity, we have two by qualitative aspects of the receptor. The receptor’s alleles and three different genotypes for each variation.