Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene

The functional significance of two unlinked human vitamin D receptor (hVDR) gene polymorphisms was evaluated in twenty human fibroblast cell lines. Ge notypes at both a Fok I restriction site (FIS) in exon II and a singlet (A) repeat in exon IX (LIS) were determined, and relative transcription activi ties of endogenous hVDR proteins were measured using a transfected, 1,25-di hydroxyvitamin D-3-responsive reporter gene. Observed activities ranged fro m 2-100-fold induction by hormone, with higher activity being displayed by the F and the L biallelic forms. Only when genotypes at both sites were con sidered simultaneously did statistically significant differences emerge. Mo reover, the correlation between hVDR activity and genotype segregated furth er into clearly defined high and low activity groups with similar genotypic distributions. These results not only demonstrate functional relevance for both the F/f and L/S common polymorphisms in hVDR, but also provide novel evidence for a third genetic variable impacting receptor potency. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.