title: Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk.
abstract: Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5' regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Janmaat
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Van De Winkel
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Manon C W
authors.initials: MC
authors.lastname: Spaander
authors.affiliation: Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Farzin
authors.initials: F
authors.lastname: Pourfarzad
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.affiliation: Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Agnieszka M
authors.initials: AM
authors.lastname: Rygiel
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Leon M G
authors.initials: LM
authors.lastname: Moons
authors.affiliation: Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Pascal P
authors.initials: PP
authors.lastname: Arp
authors.affiliation: Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Kausilia K
authors.initials: KK
authors.lastname: Krishnadath
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.|Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: Van Der Laan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D050982:GATA1 Transcription Factor / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D059372:Nucleotide Motifs; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D050982:GATA1 Transcription Factor; D018167:Receptors, Calcitriol