Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene

• Published in: Molecular and cellular endocrinology Vol. 177; no. 1; pp. 145 - 159
• Main Authors: Kerr Whitfield, G, Remus, Lenore S, Jurutka, Peter W, Zitzer, Heike, Oza, Anish K, Dang, Hope T.L, Haussler, Carol A, Galligan, Michael A, Thatcher, Michelle L, Dominguez, Carlos Encinas, Haussler, Mark R
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 25-05-2001
• Subjects: Alleles; Cell Line; Fibroblasts - cytology; Gene Frequency; Gene polymorphisms; Genes, Reporter; Genotype; Humans; Pharmacogenomics; Polymorphism, Genetic - physiology; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Transcriptional Activation - genetics; Transfection; Vitamin D receptor; Gene polymorphisms; Vitamin D receptor; Pharmacogenomics
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/S0303-7207(01)00406-3

The functional significance of two unlinked human vitamin D receptor (hVDR) gene polymorphisms was evaluated in twenty human fibroblast cell lines. Genotypes at both a
Fok I restriction site (
F/f) in exon II and a singlet (A) repeat in exon IX
(L/S) were determined, and relative transcription activities of endogenous hVDR proteins were measured using a transfected, 1,25-dihydroxyvitamin D
3-responsive reporter gene. Observed activities ranged from 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 considered simultaneously did statistically significant differences emerge. Moreover, the correlation between hVDR activity and genotype segregated further 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.