Molecular Medicine

, Volume 21, Issue 1, pp 346–354 | Cite as

Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk

  • Vincent T. Janmaat
  • Anouk van de Winkel
  • Maikel P. Peppelenbosch
  • Manon C. W. Spaander
  • André G. Uitterlinden
  • Farzin Pourfarzad
  • Hugo W. Tilanus
  • Agnieszka M. Rygiel
  • Leon M. G. Moons
  • Pascal P. Arp
  • Kausilia K. Krishnadath
  • Ernst J. Kuipers
  • Luc J. W. van der Laan
Research Article


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.

Supplementary material

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Supplementary material, approximately 567 KB.


  1. 1.
    Hvid-Jensen F, Pedersen L, Drewes AM, Sorensen HT, Funch-Jensen P. (2011) Incidence of adenocarcinoma among patients with Barrett’s esophagus. N. Engl. J. Med. 365:1375–83.CrossRefGoogle Scholar
  2. 2.
    Sikkema M, de Jonge PJ, Steyerberg EW, Kuipers EJ. (2010) Risk of esophageal adenocarcinoma and mortality in patients with Barrett’s esophagus: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 8:235–44.CrossRefGoogle Scholar
  3. 3.
    Holmes RS, Vaughan TL. (2007) Epidemiology and pathogenesis of esophageal cancer. Semin. Radiat. Oncol. 17:2–9.CrossRefGoogle Scholar
  4. 4.
    Fitzgerald RC. (2006) Molecular basis of Barrett’s oesophagus and oesophageal adenocarcinoma. Gut. 55:1810–20.CrossRefGoogle Scholar
  5. 5.
    Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. (2014) The role of vitamin D in reducing cancer risk and progression. Nat. Rev. Cancer. 14:342–57.CrossRefGoogle Scholar
  6. 6.
    Bogh MK, Schmedes AV, Philipsen PA, Thieden E, Wulf HC. (2011) Vitamin D production depends on ultraviolet-B dose but not on dose rate: a randomized controlled trial. Exp. Dermatol. 20:14–8.CrossRefGoogle Scholar
  7. 7.
    Giovannucci E. (2009) Vitamin D and cancer incidence in the Harvard cohorts. Ann. Epidemiol. 19:84–8.CrossRefGoogle Scholar
  8. 8.
    Gorham ED, et al. (2007) Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am. J. Prev. Med. 32:210–6.CrossRefGoogle Scholar
  9. 9.
    Wei MY, Garland CF, Gorham ED, Mohr SB, Giovannucci E. (2008) Vitamin D and prevention of colorectal adenoma: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 17:2958–69.CrossRefGoogle Scholar
  10. 10.
    Gandini S, et al. (2011) Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int. J. Cancer. 128:1414–24.CrossRefGoogle Scholar
  11. 11.
    Yin L, et al. (2011) Meta-analysis: serum vitamin D and colorectal adenoma risk. Prev. Med. 53:10–6.CrossRefGoogle Scholar
  12. 12.
    Larriba MJ, et al. (2011) Vitamin D receptor deficiency enhances Wnt/beta-catenin signaling and tumor burden in colon cancer. PLoS One. 6:e23524.CrossRefGoogle Scholar
  13. 13.
    Hummel DM, et al. (2013) Prevention of preneoplastic lesions by dietary vitamin D in a mouse model of colorectal carcinogenesis. J. Steroid. Biochem. Mol. Biol. 136:284–8.CrossRefGoogle Scholar
  14. 14.
    Wactawski-Wende J, et al. (2006) Calcium plus vitamin D supplementation and the risk of colorectal cancer. N. Engl. J. Med. 354:684–96.CrossRefGoogle Scholar
  15. 15.
    Chowdhury R, et al. (2014) Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 348:g1903.CrossRefGoogle Scholar
  16. 16.
    Abnet CC, et al. (2010) Circulating 25-hydroxyvitamin D and risk of esophageal and gastric cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am. J. Epidemiol. 172:94–106.CrossRefGoogle Scholar
  17. 17.
    Chen W, et al. (2007) Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers. Br. J. Cancer. 97:123–8.CrossRefGoogle Scholar
  18. 18.
    Lipworth L, et al. (2009) Dietary vitamin D and cancers of the oral cavity and esophagus. Ann. Oncol. 20:1576–81.CrossRefGoogle Scholar
  19. 19.
    Toner CD, Davis CD, Milner JA. (2010) The vitamin D and cancer conundrum: aiming at a moving target. J. Am. Diet. Assoc. 110:1492–500.CrossRefGoogle Scholar
  20. 20.
    Mulholland HG, Murray LJ, Anderson LA, Cantwell MM. (2011) Vitamin D, calcium and dairy intake, and risk of oesophageal adenocarcinoma and its precursor conditions. Br. J. Nutr. 106:732–41.CrossRefGoogle Scholar
  21. 21.
    Stolzenberg-Solomon RZ, et al. (2010) Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am. J. Epidemiol. 172:81–93.CrossRefGoogle Scholar
  22. 22.
    Trowbridge R, Sharma P, Hunter WJ, Agrawal DK. (2012) Vitamin D receptor expression and neoadjuvant therapy in esophageal adenocarcinoma. Exp. Mol. Pathol. 93:147–53.CrossRefGoogle Scholar
  23. 23.
    Trowbridge R, Mittal SK, Agrawal DK. (2013) Vitamin D and the epidemiology of upper gastrointestinal cancers: a critical analysis of the current evidence. Cancer Epidemiol. Biomarkers Prev. 22:1007–14.CrossRefGoogle Scholar
  24. 24.
    Fang Y, et al. (2005) Promoter and 3′-untranslated-region haplotypes in the vitamin D receptor gene predispose to osteoporotic fracture: the rotterdam study. Am. J. Hum. Genet. 77:807–23.CrossRefGoogle Scholar
  25. 25.
    Miyamoto K, et al. (1997) Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol. Endocrinol. 11:1165–79.CrossRefGoogle Scholar
  26. 26.
    Baker AR, et al. (1988) Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc. Natl. Acad. Sci. U. S. A. 85:3294–8.CrossRefGoogle Scholar
  27. 27.
    Crofts LA, Hancock MS, Morrison NA, Eisman JA. (1998) Multiple promoters direct the tissue-specific expression of novel N-terminal variant human vitamin D receptor gene transcripts. Proc. Natl. Acad. Sci. U. S. A. 95:10529–34.CrossRefGoogle Scholar
  28. 28.
    Trowbridge R, Mittal SK, Sharma P, Hunter WJ, Agrawal DK. (2012) Vitamin D receptor expression in the mucosal tissue at the gastroesophageal junction. Exp. Mol. Pathol. 93:246–9.CrossRefGoogle Scholar
  29. 29.
    Matusiak D, Murillo G, Carroll RE, Mehta RG, Benya RV. (2005) Expression of vitamin D receptor and 25-hydroxyvitamin D3-1α-hydroxylase in normal and malignant human colon. Cancer Epidemiol. Biomarkers Prev. 14:2370–6.CrossRefGoogle Scholar
  30. 30.
    Moons LM, et al. (2007) COX-2 CA-haplotype is a risk factor for the development of esophageal adenocarcinoma. Am J. Gastroenterol. 102:2373–9.CrossRefGoogle Scholar
  31. 31.
    DiBaise JK. (1999) The LA classification for esophagitis: a call for standardization. Am J. Gastroenterol. 94:3403–4.PubMedGoogle Scholar
  32. 32.
    Pfaffl MW. (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29:e45.CrossRefGoogle Scholar
  33. 33.
    Wall L, deBoer E, Grosveld F. (1988) The human beta-globin gene 3′ enhancer contains multiple binding sites for an erythroid-specific protein. Genes Dev. 2:1089–100.CrossRefGoogle Scholar
  34. 34.
    Messeguer X, et al. (2002) PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 18:333–4.CrossRefGoogle Scholar
  35. 35.
    Farre D, et al. (2003) Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 31:3651–3.CrossRefGoogle Scholar
  36. 36.
    Merika M, Orkin SH. (1993) DNA-binding specificity of GATA family transcription factors. Mol. Cell. Biol. 13:3999–4010.CrossRefGoogle Scholar
  37. 37.
    Uhlen M, et al. (2010) Towards a knowledge-based Human Protein Atlas. Nat. Biotechnol. 28:1248–50.CrossRefGoogle Scholar
  38. 38.
    Boyle MJ, Seaver EC. (2008) Developmental expression of foxA and gata genes during gut formation in the polychaete annelid, Capitella sp. I. Evol. Dev. 10:89–105.CrossRefGoogle Scholar
  39. 39.
    Haveri H, et al. (2008) Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa. BMC Gastroenterol. 8:9.CrossRefGoogle Scholar
  40. 40.
    Hyland PL, et al. (2014) Global changes in gene expression of Barrett’s esophagus compared to normal squamous esophagus and gastric cardia tissues. PLoS One. 9:e93219.CrossRefGoogle Scholar
  41. 41.
    Milano F, et al. (2007) Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells. Gastroenterology. 132:2412–21.CrossRefGoogle Scholar
  42. 42.
    Gobel F, et al. (2009) Reciprocal role of GATA-1 and vitamin D receptor in human myeloid dendritic cell differentiation. Blood. 114:3813–21.CrossRefGoogle Scholar
  43. 43.
    Chang CK, et al. (2012) Vitamin D receptor gene variants and esophageal adenocarcinoma risk: a population-based case-control study. J. Gastrointest. Cancer. 43:512–7.CrossRefGoogle Scholar

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Authors and Affiliations

  • Vincent T. Janmaat
    • 1
  • Anouk van de Winkel
    • 1
  • Maikel P. Peppelenbosch
    • 1
  • Manon C. W. Spaander
    • 1
  • André G. Uitterlinden
    • 2
  • Farzin Pourfarzad
    • 3
  • Hugo W. Tilanus
    • 4
  • Agnieszka M. Rygiel
    • 5
  • Leon M. G. Moons
    • 1
  • Pascal P. Arp
    • 2
  • Kausilia K. Krishnadath
    • 5
  • Ernst J. Kuipers
    • 1
    • 2
  • Luc J. W. van der Laan
    • 4
  1. 1.Department of Gastroenterology and HepatologyErasmus MC-University Medical CenterRotterdamThe Netherlands
  2. 2.Department of Internal Medicine, Epidemiology and Clinical ChemistryErasmus MC-University Medical CenterRotterdamThe Netherlands
  3. 3.Department of Cell BiologyErasmus MC-University Medical CenterRotterdamThe Netherlands
  4. 4.Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery (LETIS)Erasmus MC-University Medical CenterRotterdamThe Netherlands
  5. 5.Center for Experimental Molecular MedicineAcademic Medical CenterAmsterdamThe Netherlands

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