Annotated PGx Gene Information for VDR

Submitted by: Audrey H. Poon, Charlotte Brasch-Andersen, Augusto A. Litonjua, Benjamin A. Raby, Scott T. Weiss (PHAT)
Reviewed by: Reviewed
Submitted date: May 22, 2006

Gene HGNC Name:	VDR
Gene Common Name:	VDR
Introductory Information:	The Vitamin D receptor (VDR) binds the active form of vitamin D (1,25-dihydroxyvitamin D₃). It belongs to the family of trans-acting transcriptional regulatory factors and shows sequence similarity to the steroid and thyroid hormone receptors. The gene was cloned by Baker et al. in 1988 [PMID: 2835767] and maps to chromosome 12q13.11. It consists of 9 exons with at least 6 isoforms of exon 1, spans 63.5 kb and encodes a 427-amino acid protein [PMID: 9212063]. Alternative splicing results in multiple transcript variants encoding the VDR protein of different lengths [PMID: 9724737]. In addition, a T>C base change (rs2228570, alias FokI) eliminates the methionine start codon at exon 2 and the encoded protein is shortened by 3 amino acids [PMID: 1652893]. Another variant, commonly known as Cdx2 due to its location in the binding site of transcription factor Cdx2, is located in the promoter region, upstream of exon 1e [PMID: 9933478]. Functional analyses showed that the A to G base substitution eliminates the Cdx binding site and reduces transcriptional activity of VDR to 70% of the A allele in the small intestine [PMID: 11450701]. The interaction of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) with VDR modulates many biological activities of the neural, immune, and endocrine systems, including calcium and phosphorous homeostasis, apoptosis and cell differentiation (reviewed in [PMID: 12520530, 7626516]). Microarray analyses using different human cell lines have identified over one hundred genes with vitamin D response elements at the promoter regions, all potential targets of the 1,25(OH)₂D₃- VDR complex [PMID: 16002434, 14996990, 12040012]. Genes which have been confirmed to be VDR regulated include osteopontin [PMID: 9823334], 25-Dihydroxyvitamin D-24-hydroxylase [PMID: 9228086], and amphiregulin [PMID: 14996990]. A more comprehensive review of over 60 confirmed VDR regulated genes in various cancer cells has been published [PMID: 15798098]. Three LD blocks within the gene have been localized. Block "A" at the 3' end of exon 9 spans approximately 10.5 kb, block "B" spans 40 kb and VDR exons 3-9 and block "C" contains exon 1. Block "B" and "C" are separated by a 1.3 kb LD-breaking spot including VDR exon 2 and the FokI SNP while a 5.7 kb LD-breaking spot separates block "A" and "B" [PMID: 15175274]. The three widely studied variants BsmI, ApaI and TaqI are located to block B and they are often analyzed together as haplotypes in disease/phenotype association studies [PMID: 8864898]; however, further analysis of this genomic area showed that these three variants do not capture all the information in the block [PMID: 15175274]. (Note on the nomenclature of the variants, the alleles are conventionally defined by capital letters in the absence of a restriction site and small letters in the presence of a given restriction site, e.g. TaqI T and C alleles are named T and t, respectively.) Due to the pleiotrophic effect the 1,25(OH)₂D₃- VDR complex exerts, its genetic variants have been found to be associated with a variety of diseases/phenotypes (see below); however, there are inconsistent results among these studies. Phenotypes/disease which have had at least 2 reports of association include asthma [PMID: 15282199, 15282200], BMD [PMID: 8970884, 10367030], breast cancer [PMID: 16214913, 15328186], prostate cancer [PMID: 8797574, 10667581], insulin-dependent diabetes mellitus (IDDM) [PMID: 10792336, 10868975], tuberculosis (TB) [PMID: 15478069, 15141734], and osteoporosis therapy efficacy [PMID: 15861036 ( PA135307235), 15739035], psoriasis [PMID: 15864137, 9886274] and hyperparathyroidism [PMID: 9070272, 9740163]
Key PubMed IDs:	2835767, 9212063, 15175274, 15282199, 15282200, 9724737, 1652893, 1575274, 12520530, 7626516
Key Pathways:	Etoposide pathway
Drugs/Substrates:	1,25-dihydroxyvitamin D₃ [PMID: 333287, 333288] and Vitamin D analogs (e.g., calcitriol, calcipotriol, talcalcitol, maxacalcitol, EB 1089 and alfacalcidol) (reviewed in PMID: 15798098).
Phenotypes/Diseases:	asthma [PMID: 15282199, 15282200]; allergy skin test response [PMID: 15282199], Vitamin D-dependent rickets [PMID: 2849209/ PA130757259, 1652893], osteocalcin levels [PMID: 8797122, 1353882], bone mineral density (BMD) [PMID: 8970884, 10367030, 15040830], osteoporosis [PMID: 16252240, 8782780, 11204438], breast cancer [PMID: 16214913, 15328186, 10680726], prostate cancer [PMID: 8797574, 10667581, 12181642], insulin-dependent diabetes mellitus [PMID: 10792336, 10868975, 10792336], tuberculosis [PMID: 15478069, 15141734, 10696983], acquired immunodeficiency syndrome [PMID: 15225772, 11679916], psoriasis, myocardial infarction [PMID: 16207551], and osteoporosis therapy efficacy [PMID: 15861036 ( PA135307235 ), 15739035]
Important Variants:	VDR:Cdx2 , VDR:FokI, VDR:rs3782905 , VDR:rs2239179 , VDR:rs1540339 , VDR:rs2239185, VDR:BsmI, VDR:ApaI , VDR:TaqI

The PGRN is financially supported by grants from NIGMS, NHLBI, NHGRI, NIEHS, NCI, and NLM within the NIH, HHS. PharmGKB is managed at Stanford University. This work is supported by the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374). ©2001-2008 PharmGKB.