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.
Highlights
The incidence of esophageal adenocarcinoma (EAC) in Western Europe and North America has shown an upward trend for many decades
EAC often arises within Barrett esophagus (BE) [1,2], a metaplastic condition of the distal esophagus, in which through longstanding gastroesophageal reflux esophagitis (RE), the normal squamous epithelium is replaced by columnar epithelium
Human Patients and Healthy Controls The association between vitamin D receptor (VDR) alleles and esophageal disease was analyzed in a group of 708 patients with RE, BE or EAC who visited the endoscopy unit of the Erasmus Medical Center Rotterdam or the IJsselland Hospital in Capelle aan den IJssel between November 2002 and February 2005 [30]
Summary
The incidence of esophageal adenocarcinoma (EAC) in Western Europe and North America has shown an upward trend for many decades. In Western countries, the prevalence of BE has increased dramatically since the 1970s [3], which explains the increasing incidence of EAC. Vitamins and antioxidants are believed to be key dietary components, some of which pose anticarcinogenic action [5]. Vitamin D is a micronutrient and is the precursor to the steroid hormone calcitriol. It is obtained from dietary sources, but can be produced endogenously under the influence of solar ultraviolet-B radiation [6]. The vitamin D receptor (VDR) is expressed in a variety of tissues that are not involved in RESEARCH ARTICLE
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