Skip to main content

Advertisement

SpringerLink
Log in

Vitamin D receptor haplotypes protect against development of colorectal cancer

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

We investigated the association of vitamin D receptor polymorphisms and colorectal cancer incidence in a Caucasian population.

Methods

Frequencies of the vitamin D receptor gene polymorphisms 23005G>A (CDX-2), 27823C>T (FokI), 60890G>A (BsmI), 61050G>A (Tru9I), 61888G>T (ApaI), and 61968T>C (TaqI) were determined in a series of 256 colorectal cancer patients and 256 patients without malignant disease (case-control study) using polymerase chain reaction and restriction fragment length polymorphism genotyping assays (PCR-RFLP). Haplotype analysis based on the six genetic loci was applied to the received genotypes.

Results

Pairwise linkage disequilibrium between BsmI, ApaI, TaqI, and Tru9I was confirmed (P < 0.001). Allele frequencies did not differ between the groups. There was no association between any single variant and colorectal cancer. However, haplotypes BsmI(G)#TaqI(C) and BsmI(A)#TaqI(T) were inversely associated with colorectal cancer incidence (P < 0.001), the odds being 15.0 times smaller [odds ratio (OR) 0.067; 95% confidence interval (CI), 0.016–0.284] and 5.3 times smaller (OR 0.188; 95% CI 0.077–0.461), respectively, compared with noncarriers.

Conclusion

Our findings suggest that vitamin D receptor haplotypes BsmI(G)#TaqI(C) and BsmI(A)#TaqI(T) have a protective effect against colorectal cancer in Caucasians.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Globocan (2002) IARC International Agency for Research on Cancer

  2. Garland CF, Garland FC (1980) Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 9:227–231

    Article  PubMed  CAS  Google Scholar 

  3. Garland CF, Garland FC, Gorham ED (1999) Calcium and vitamin D. Their potential roles in colon and breast cancer prevention. Ann N Y Acad Sci 889:107–119

    Article  PubMed  CAS  Google Scholar 

  4. American Cancer Society (2001) Cancer facts and figures. Atlanta,GA

  5. Garland CF, Garland FC, Gorham ED (1991) Can colon cancer incidence and death rates be reduced with calcium and vitamin D? Am J Clin Nutr 54:193–201

    Google Scholar 

  6. Zhao X, Feldman D (1993) Regulation of vitamin D receptor abundance and responsiveness during differentiation of HT-29 human colon cancer cells. Endocrinology 132(4):1808–1814

    Article  PubMed  CAS  Google Scholar 

  7. Vandewalle B, Adenis A, Hornez L, Revillion F, Lefebvre J (1994) 1,25-dihydroxyvitamin D3 receptors in normal and malignant human colorectal tissues. Cancer Lett 86:67–73

    Article  PubMed  CAS  Google Scholar 

  8. Giuliano AR, Franceschi RT, Wood RJ (1991) Characterization of the vitamin D receptor from the Caco-2 human colon carcinoma cell line: effect of cellular differentiation. Arch Biochem Biophys 285:261–269

    Article  PubMed  CAS  Google Scholar 

  9. Kane KF, Langman MJ, Williams GR (1995) 1,25-Dihydroxyvitamin D3 and retinoid X receptor expression in human colorectal neoplasms. Gut 36(2):255–258

    Article  PubMed  CAS  Google Scholar 

  10. Evans SR, Nolla J, Hanfelt J, Shabahang M, Nauta RJ, Shchepotin IB (1998) Vitamin D receptor expression as a predictive marker of biological behavior in human colorectal cancer. Clin Cancer Res 4(7):1591–1595

    PubMed  CAS  Google Scholar 

  11. Langdahl BL, Gravholt CH, Brixen K, Eriksen EF (2000) Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures. Eur J Clin Invest 30:608–617

    Article  PubMed  CAS  Google Scholar 

  12. Douroudis K, Tarassi K, Ioannidis G, Giannakopoulos F, Moutsatsou P, Thalassinos N, Papasteriades C (2003) Association of vitamin D receptor gene polymorphisms with bone mineral density in postmenopausal women of Hellenic origin. Maturitas 45:191–197

    Article  PubMed  CAS  Google Scholar 

  13. Zhang YY, Long JR, Liu PY, Liu YJ, Shen H, Zhao LJ, Deng HW (2003) Estrogen receptor alpha and vitamin D receptor gene polymorphisms and bone mineral density: association study of healthy pre- and postmenopausal Chinese women. Biochem Biophys Res Commun 308:777–783

    Article  PubMed  CAS  Google Scholar 

  14. Kim JG, Kwon JH, Kim SH, Choi YM, Moon SY, Lee JY (2003) Association between vitamin D receptor gene haplotypes and bone mass in postmenopausal Korean women. Am J Obstet Gynecol 189:1234–1240

    Article  PubMed  CAS  Google Scholar 

  15. Uitterlinden AG, Weel AE, Burger H, Fang Y, van Duijn CM, Hofman A, van Leeuwen JP, Pols HA (2001) Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture. J Bone Miner Res 16:379–385

    Article  PubMed  CAS  Google Scholar 

  16. Pacini S, Nicastro L, Aterini S, Stefani P, Ruggiero M (1996) The determination of BB genotype of vitamin D receptors identifies patients at risk for osteoporosis. Radiol Med (Torino) 92:520–524

    CAS  Google Scholar 

  17. Gyorffy B, Vasarhelyi B, Krikovszky D, Madacsy L, Tordai A, Tulassay T, Szabo A (2002) Gender-specific association of vitamin D receptor polymorphism combinations with type 1 diabetes mellitus. Eur J Endocrinol 147:803–808

    Article  PubMed  CAS  Google Scholar 

  18. Pani MA, Knapp M, Donner H, Braun J, Baur MP, Usadel KH, Badenhoop K (2000) Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes 49:504–507

    Article  PubMed  CAS  Google Scholar 

  19. Skrabic V, Zemunik T, Situm M, Terzic J (2003) Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the Dalmatian population. Diabetes Res Clin Pract 59:31–35

    Article  PubMed  CAS  Google Scholar 

  20. Oh JY, Barrett-Connor E (2002) Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo Study. Metabolism 51:356–359

    Article  PubMed  CAS  Google Scholar 

  21. Halsall JA, Osborne JE, Pringle JH, Hutchinson PE (2005) Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis. Pharmacogenet Genomics 15:349–355

    Article  PubMed  CAS  Google Scholar 

  22. Park BS, Park JS, Lee DY, Youn JI, Kim IG (1999) Vitamin D receptor polymorphism is associated with psoriasis. J Invest Dermatol 112:113–116

    Article  PubMed  CAS  Google Scholar 

  23. Nieto G, Barber Y, Rubio MC, Rubio M, Fibla J (2004) Association between AIDS disease progression rates and the Fok-I polymorphism of the VDR gene in a cohort of HIV-1 seropositive patients. J Steroid Biochem Mol Biol 89–90(1–5):199–207

    Article  PubMed  CAS  Google Scholar 

  24. Guy M, Lowe LC, Bretherton-Watt D, Mansi JL, Colston KW (2003) Approaches to evaluating the association of vitamin D receptor gene polymorphisms with breast cancer risk. Recent Results Cancer Res 164:43–54

    PubMed  CAS  Google Scholar 

  25. Sillanpaa P, Hirvonen A, Kataja V, Eskelinen M, Kosma VM, Uusitupa M, Vainio H, Mitrunen K (2004) Vitamin D receptor gene polymorphism as an important modifier of positive family history related breast cancer risk. Pharmacogenetics 14:239–245

    Article  PubMed  Google Scholar 

  26. Huang SP, Chou YH, Wayne Chang WS, Wu MT, Chen YY, Yu CC, Wu TT, Lee YH, Huang JK, Wu WJ, Huang CH (2004) Association between vitamin D receptor polymorphisms and prostate cancer risk in a Taiwanese population. Cancer Lett 207:69–77

    Article  PubMed  CAS  Google Scholar 

  27. Ban Y, Taniyama M (2000) Vitamin D receptor gene polymorphism is associated with Graves’ disease in the Japanese population. J Clin Endocrinol Metab 85:4639–4643

    Article  PubMed  CAS  Google Scholar 

  28. Carling T, Rastad J, Akerstrom G, Westin G (1998) Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors. J Clin Endocrinol Metab 83:2255–2259

    Article  PubMed  CAS  Google Scholar 

  29. Grau MV, Baron JA, Sandler RS, Haile RW, Beach ML, Church TR, Heber D (2003) Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst 95:1765–1771

    PubMed  CAS  Google Scholar 

  30. Park K, Woo M, Nam J, Kim JC (2006) Start codon polymorphisms in the vitamin D receptor and colorectal cancer risk. Cancer Lett 237(2):199–206

    Article  PubMed  CAS  Google Scholar 

  31. Slattery ML, Yakumo K, Hoffman M, Neuhausen S (2001) Variants of the VDR gene and risk of colon cancer (United States). Cancer Causes Control 12:359–364

    Article  Google Scholar 

  32. Sweeney C, Curtin K, Murtaugh MA, Caan BJ, Potter JD, Slattery ML (2006) Haplotype analysis of common vitamin D receptor variants and colon and rectal cancers. Cancer Epidemiol Biomarkers Prev 15(4):744–749

    Article  PubMed  CAS  Google Scholar 

  33. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  34. Collins JE, Heward JM, Nithiyananthan R, Nejentsev S, Todd JA, Franklyn JA, Gough SC (2004) Lack of association of the vitamin D receptor gene with Graves’ disease in UK Caucasians. Clin Endocrinol (Oxf) 60:618–624

    Article  CAS  Google Scholar 

  35. Malecki MT, Frey J, Moczulski D, Klupa T, Kozek E, Sieradzki J (2003) Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population. Exp Clin Endocrinol Diabetes 111:505–509

    Article  PubMed  CAS  Google Scholar 

  36. Kadiyska T, Yakulov T, Kaneva R, Nedin D, Alexandrova A, Gegova A, Savov A, Mitev V, Kremensky I (2006) Vitamin D and estrogen receptor gene polymorphisms and the risk of colorectal cancer in Bulgaria. Int J Colorectal Dis 22:395–400

    Article  PubMed  Google Scholar 

  37. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M et al (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391

    Article  PubMed  CAS  Google Scholar 

  38. Liu PY, Zhang YY, Lu Y, Long JR, Shen H, Zhao LJ, Xu FH, Xiao P, Xiong DH, Liu YJ, Recker RR, Deng HW (2005) A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases. J Med Genet 42:221–227

    Article  PubMed  CAS  Google Scholar 

  39. Thakkinstian A, D’Este C, Attia J (2004) Haplotype analysis of VDR gene polymorphisms: a meta-analysis. Osteoporos Int 15:729–734

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. G. Laschinski for thorough review of the manuscript. This project was supported by the German Federal Ministry of Education and Research (BMBF), (INNO Regio Project, Grant 03I4507, Pharmakogenomische Optimierung der Arzneitherapie und Arzneimittelentwicklung).

Author information

Authors and Affiliations

  1. Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany

    Jana Flügge, Solveigh Krusekopf, Mark Goldammer, Elena Osswald, Werner Terhalle, Uwe Malzahn & Ivar Roots

  2. CENiMED GmbH, Center for Individualized Medicine - Clinical Pharmacogenomics, Robert-Rössle-Str. 10, 13125, Berlin-Buch, Germany

    Jana Flügge, Solveigh Krusekopf, Mark Goldammer, Werner Terhalle, Uwe Malzahn & Ivar Roots

Authors
  1. Jana Flügge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Solveigh Krusekopf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark Goldammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elena Osswald
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Werner Terhalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Uwe Malzahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ivar Roots
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Solveigh Krusekopf.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flügge, J., Krusekopf, S., Goldammer, M. et al. Vitamin D receptor haplotypes protect against development of colorectal cancer. Eur J Clin Pharmacol 63, 997–1005 (2007). https://doi.org/10.1007/s00228-007-0367-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-007-0367-4

Keywords

Search

Navigation