Association between Circulating Vitamin D, the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

  • Atoum, Manar Fayiz (Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Hashemite University) ;
  • Tchoporyan, Melya Nizar (Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Hashemite University)
  • Published : 2014.09.15


Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form $1,25(OH)_2D$ to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study wass to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and Methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by paired t-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancer patients (8.34 ng/ml) compared to the healthy control group (21.02ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT ($8.91{\pm}4.31$) and Tt ($9.15{\pm}5.25$) genotypes compared to control ($21.3{\pm}8.31$) and ($19.3{\pm}7.68$); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.


  1. Anderson MG, Nakane M, Ruan X, Kroeger PE, Wu-Wong JR (2006). Expression of VDR and CYP24A1 mRNA in human tumors. Cancer Chemother Pharmacol, 57, 234-40.
  2. Arai H, Miyamoto KI, Yoshida M, et al (2001). The polymorphism in the caudal-related hemodomain protein Cdx-2 binding elements in the human vitamin D receptor gene. J Bone Miner Res, 16, 1256-64.
  3. Ashktorab H, Nguza B, Fatemi M, et al (2011). Case-control study of vitamin D, dickkopfhomolog 1 (DKK1) gene methylation, VDR gene polymorphism and the risk of colon adenoma in african americans. PLoS One, 6, 25314.
  4. Bai YH, Lu H, Hong D, et al (2012). Vitamin D receptor gene polymorphisms and colorectal cancer risk:a systematic metaanalysis. World J Gastroenterol, 18, 1672-9.
  5. Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick M.F (2013). Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab, 98, 973-9.
  6. Bid HK, Mishra DK, Mittal RD (2005). Vitamin-D receptor (VDR) gene (Fok1, Taq1 and Apa1) polymorphisms in healthy individuals from north Indian population. Asian Pac J Cancer Prev, 6, 147-52.
  7. Bhanushali AA, Lajpal N, Kulkarni SS, et al (2009). Frequency of fokI and taqI polymorphism of vitamin D receptor gene in Indian population and its association with 25-hydroxyvitamin D levels. Indian J Hum Genet, 15, 108-13.
  8. Bouillon R, Carmeliet G, Verlinden L, et al (2008).Vitamin D and human health: lessons from vitamin D receptor null mice. Endocrine reviews, 29, 726-76.
  9. Deeb KK, Trump DL, Johnson CS (2007). Vitamin D signaling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer, 7, 684-700.
  10. Byers SW, Rowlands T, Beildeck M, Bong YS (2012). Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment. Rev Endocr Metab Disord, 13, 31-8.
  11. Carlberg C (2003). Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. Recent Results Cancer Res, 164, 29-42.
  12. Carlberg C, Seuter S (2009). A genomic perspective on vitamin D signaling. Anticancer Res, 29, 3485-93.
  13. Cunningham D, Atkin W, Lenz HJ, et al (2010). Colorectal cancer. The Lancet, 375, 1030-47.
  14. Dilmec F, Ozgonul A, Akkafa F, (2009). Determination of ApaI and TaqI polymorphisms of VDR gene in a group of Turkish patients with colorectal cancer. Internat J Hematol Oncol, 19, 18-22.
  15. Freedman DM, Looker AC, Chang SC, Graubard BI. (2007). Prospective study of serum vitamin D and cancer mortality in the United States. J Nat Cancer Inst, 99, 1594-602.
  16. Gunduz M, Cacyna C, Toptas B, et al (2012). Association of vitamin D receptor gene polymorphisms with colon cancer. Genet Test Mol Biomarkers, 16,1058-61.
  17. Haussler MR, Jurutka PW, Mizwicki M, Norman AW (2011).Vitamin D receptor (VDR)-mediated actions of $1\alpha$,25(OH)2vitamin D3: Genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab, 25, 543-59.
  18. Flugge J, Krusekopf S, Goldammer M, et al (2007). Vitamin D receptor haplotypes protect against development of colorectal cancer. Eur J Clin Pharmacol, 63, 997-1005.
  19. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al (2011). Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 96, 1911-30.
  20. Ingles SA, Ross RK, Yu MC, et al (1997). Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Nat Cancer Inst, 89,166-70
  21. Jenab M, Bueno-de-Mesquita HB, Ferrari P, et al (2010). Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ, 340, 5500.
  22. Jehan F, d'Alesio A, Garabedian M (2007). Exons and functional regions of the human vitamin D receptor gene around and within the main 1a promoter are well conserved among mammals. J Steroid Biochem Mol Boil, 103, 361-7.
  23. Jones G (2008). Pharmacokinetics of vitamin D toxicity. American J Clin Nutr, 88, 582-6.
  24. Jordan Cancer Registry, Cancer Incidence In Jordan 2010.
  25. Kang K, Lee S, Jeon E, et al (2011). Emerging role of vitamin D in colorectal cancer. World J Gastrointest Oncol, 3, 123-7.
  26. Kostner K, Denzer N, Muller CS, et al (2009). The Relevance of vitamin D receptor gene polymorphisms for cancer: a review of literature. Anticancer Research, 29, 3511-36.
  27. Labianca R, Nordlinger B, Beretta GD, Brouquet A, Cervantes A (2010). Guidelines working group "Primary colon cancer: ESMO clinical practice guidelines for diagnosis, adjuvant treatment and follow-up". Ann Oncol, 21, 70-7.
  28. Larriba MJ, Munoz A (2005). SNAIL vs vitamin D receptor expression in colon cancer: therapeutics implications. Br J Cancer, 92, 985-9.
  29. Lee JE, Li H, Chan AT, et al (2011). Circulatory levels of vitamin D and colon and rectal cancer: Physicians health study and a meta-analysis of prospective studies. Cancer Prev Res, 4, 735-43.
  30. Lips P (2007).Vitamin D status and nutrition in Europe and Asia. J Steroid Biochem Mol Biol, 103, 620-5.
  31. Mallah EM, Arafat TA, Hamad MF, et al (2011). Plasma concentrations of 25-hydroxyvitamin D among Jordanians: Effect of biological and habitual factors on vitamin D status. BMC Clin Pathol, 4, 11.
  32. Marcinkowska E (2001). A run for a membrane vitamin D receptor. Biol Signals Recept, 10, 341-9.
  33. Matusiak D, Murillo G, Carroll RE, Mehta RG, a Benya RV (2005). Expression of vitamin D receptor and 25-hydroxyvitaminD3-1a-hydroxylase in normal and malignant human colon. Cancer Epidemiol Biomarkers Prev, 14, 2370-6.
  34. Minamitani K, Takahashi Y, Mingawa M, Yasuda T, Niimi H (1998). Difference in height associated with a translation start site polymorphism in the vitamin D receptor gene. Pediatr Res, 44, 628-32.
  35. Natrah MS, Ezat S, Syed MA, Rizal AM, Saperi S (2014). Quality of life in Malaysian colorectal cancer patients: a preliminary result. Asian Pac J Cancer Prev, 13, 957-62.
  36. Onen IH, Ekmekci A, Eroglu M, et al (2008). Association of genetic polymorphism in vitamin D receptor gene and susceptibility to sporadic prostate cancer. Exp Biol Med (Maywood), 233, 1608-14.
  37. Pereira F, Larriba MJ, Munoz A (2012). Vitamin D and colon cancer. Endocr relat cancer, 19, 51-71
  38. Rasool S, Kadla SA, Khan T, et al (2013). Association of a VDR gene polymorphism with risk of colorectal cancer in Kashmir. Asian Pac J Cancer Prev, 14, 5833-7
  39. Raimondi S, Johansson H, Maisonneuve P, Gandini S (2009). Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis, 30, 1170-80
  40. Richetta AG, Silvestri V, Giancristoforo S, et al (2014). A-1012G promoter polymorphism of vitamin D receptor gene is associated with psoriasis risk and lower allele-specific expression. DNA Cell Biol, 33, 102-9.
  41. Ross AC, Taylor CL, Yaktine AL, Del valle HB (2011). Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press.
  42. Slattery ML (2007).Vitamin D receptor gene (VDR) associations with cancer. Nutr Rev, 65, 102-4.
  43. Slattery ML, Yakumo K, Hoffman M, Neuhausen S (2001). Variants of the VDR gene and risk of colon cancer (United States). Cancer Causes Control, 12, 359-64.
  44. Seifert M, Tilgen W, Reichrath J (2009). Expression of 25-hydroxyvitamin D-1alpha-hydroxylase (1alphaOHase, CYP27B1) splice variants in HaCaT keratinocytes and other skin cells: modulation by culture conditions and UV-B treatment in vitro. Anticancer Res, 29, 3659-67.
  45. Thacher TD, Clarke BL (2010).Vitamin D insufficiency. Mayo Clin Proc, 86, 50-60.
  46. Tsiaras WG, Weinstock MA (2011). Factors influencing vitamin D status. Acta Derm Venereol, 91, 115-24.
  47. Verstuyf A, Carmeliet G, Bouillon R, Mathieu C (2010).Vitamin D: a pleiotropic hormone. Kidney Int, 78, 140-5.
  48. Vuolo L, Di Somma C, Faggiano A, Colao A (2012). Vitamin D and cancer. Front Endocrinol, 3, 58.
  49. Welsh J (2012). Cellular and molecular effects of vitamin D on carcinogenesis. Arch Biochem Biophys, 523, 107-14.
  50. Woolcott CG, Wilkens LR, Nomura AM, et al (2010). Plasma 25-hydroxyvitamin D levels and the risk of colorectal cancer: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev, 19, 130-4.
  51. Yaylim-Eraltan I, Arzu Ergen H, Arikan S, et al (2007). Investigation of the VDR gene polymorphisms association with susceptibility to colorectal cancer. Cell Biochem Funct, 25,731-7.
  52. Yu K, Yang J, Jiang Y, Song R, Lu Q. (2014). Vitamin D receptor BsmI polymorphism and colorectal cancer risk: an updated analysis. Asian Pac J Cancer Prev, 15, 4801-7.
  53. Zheng W, Wong KE, Zhang Z, et al (2012). Inactivation of the vitamin D receptor in APCmin/1 mice reveals a critical role for the vitamin D receptor in intestinal tumor growth. Int J Cancer, 130, 10-9.
  54. Zinser GM, Mceleney K, Welsh J (2003). Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockout mice. Mol Cell Endocrinol, 200, 1-2.

Cited by

  1. Associations between Vitamin D Receptor (VDR) Gene Polymorphisms and Colorectal Cancer Risk and Effect Modifications of Dietary Calcium and Vitamin D in a Japanese Population vol.16, pp.5, 2015,
  2. The Fok1 Vitamin D Receptor Gene Polymorphism and 25(OH) D Serum Levels and Prostate Cancer among Jordanian Men vol.16, pp.6, 2015,
  3. Association of Dietary Vitamin D and Calcium With Genetic Polymorphisms in Colorectal Neoplasia vol.20, pp.2, 2015,
  4. Association of Vitamin D Receptor Gene Polymorphisms with Colorectal Cancer in a Saudi Arabian Population vol.11, pp.6, 2016,
  5. Evaluation of the correlation between serum levels of vitamin D and vitamin D receptor gene polymorphisms in an Egyptian population vol.55, pp.12, 2016,
  6. 25-Hydroxyvitamin D Status and Risk for Colorectal Cancer and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Epidemiological Studies vol.14, pp.2, 2017,
  7. Positive correlation between vitamin D receptor gene FokI polymorphism and colorectal cancer susceptibility in South-Khorasan of Iran vol.119, pp.10, 2018,
  8. Vitamin D Receptor TaqI Polymorphism Is Associated With Reduced Follicle Number in Women Utilizing Assisted Reproductive Technologies vol.9, pp.1664-2392, 2018,