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Vitamin D receptor (VDR) is a nuclear hormone receptor that acts as a transcriptional regulator in response to circulating 1,25 dihydroxyvitamin D3, the active hormonal form of vitamin D. VDR gene polymorphism (VDRGP) have been extensively studied in different diseases, with over 700 primary research articles, although this has focused mainly on the same markers. The VDRGP experience, with its huge literature and appearance of apparently contradictory reports each month, may provide an example of what to expect with other genes in the growing field of analysis of common gene polymorphisms with complex common disorders. Morita et al. provide a typical example of a moderately sized population study of the relationship of VDRGP to bone density and rate of bone loss in Japanese.1 Reviewing the VDRGP literature is beyond the scope of this commentary which will only refer to a limited number of publications. For those interested, Zmuda et al. provide two comprehensive reviews of the literature of VDR related to disease.2,3 Suffice to say that VDRGP have shown positive association to a wide range of divergent diseases, and due to the pleiotropic mode of action of a nuclear-hormone receptor such as the VDR, plausible molecular scenarios of involvement can be constructed for many different diseases. In fact, if functional genetic polymorphism occurs in a transcriptional regulator, one should expect pleiotropism, due to the fact that VDR controls the expression of a large and unknown number of subordinate genes, in both positive and negative senses and in cell-specific manners. The VDR protein is at the centre of the vitamin D endocrine system, a complex physiological system with substantial feedback regulatory mechanisms involved in maintaining serum calcium and 1,25 dihydroxyvitamin D3 within narrow bounds and now known to affect a large number of organs.4 It is possible that the self-regulatory nature of the VDR endocrine system moderates the effect of VDRGP. VDR gene polymorphisms are looking for phenotypes, and judging from the literature, are related to numerous different traits, reflecting pleiotropism. Therefore, although literature has accumulated concerning VDR and bone mineral density (BMD) in particular, this may not necessarily be the most potent effect of genetic variation in VDR.

Commentary: Vitamin D receptor polymorphism and bone mineral density: effect size in Caucasians means detection is uncertain in small studies