Tumor Biology

, Volume 37, Issue 5, pp 6379–6387 | Cite as

Genetic variation in vitamin D-related genes and risk of breast cancer among women of European and East Asian descent

  • Joy Shi
  • Anne Grundy
  • Harriet Richardson
  • Igor Burstyn
  • Johanna M. Schuetz
  • Caroline A. Lohrisch
  • Sandip K. SenGupta
  • Agnes S. Lai
  • Angela Brooks-Wilson
  • John J. Spinelli
  • Kristan J. Aronson
Original Article


Studies of vitamin D-related genetic variants and breast cancer have been inconsistent. This study aimed to investigate associations of vitamin D-related polymorphisms and breast cancer risk among European and East Asian women and potential interactions with menopausal status and breast tumour subtypes. Data from a case–control study of breast cancer (1037 cases and 1050 controls) were used to assess relationships between 21 polymorphisms in two vitamin D-related genes (GC and VDR) and breast cancer risk. Odds ratios were calculated in stratified analyses of European and East Asian women, using logistic regression in an additive genetic model. An interaction term was used to explore modification by menopausal status. Polytomous regression was used to assess heterogeneity by breast tumour subtype. False discovery rate adjustments were conducted to account for multiple testing. No association was observed between GC or VDR polymorphisms and breast cancer risk. Modification of these relationships by menopausal status was observed for select polymorphisms in both Europeans (VDR rs4328262 and rs11168292) and East Asians (GC rs7041 and VDR rs11168287). Heterogeneity by tumour subtype was seen for three VDR polymorphisms (rs1544410, rs7967152 and rs2239186) among Europeans, in which associations with ER−/PR−/HER2+ tumours, but not with other subtypes, were observed. In conclusion, associations between vitamin D-related genetic variants and breast cancer were not observed overall, although the relationships between vitamin D pathway polymorphisms and breast cancer may be modified by menopausal status and breast tumour subtype.


Vitamin D-related genes Polymorphisms Breast cancer Tumour subtype Case–control 



The authors thank all participants for their contribution to this research study. We are grateful for the assistance from Dr. Linda Warren, Dr. Philip Switzer, Caroline Speers, the BC Cancer Registry, the Screening Mammography Program of BC, Agnes Bauzon, Alegria Imperial, Betty Hall, Lina Hsu, Maria Andrews, Teresa Pavlin, Dr. Ross Walker, Dr. Ralph George, Celine Morissette, Jane Warner, Hilary Rimmer, Meghan Hamel and Annie Langley with participant recruitment and data collection in Vancouver and Kingston. The authors thank the genotyping services provided by the McGill University and Genome Quebec Innovation Centre, Montreal, Canada.

Compliance with ethical standards

Conflicts of interest



The Canadian Breast Cancer Study was supported by the Canadian Institutes of Health Research (Grant #69036).

Supplementary material

13277_2015_4417_MOESM1_ESM.doc (64 kb)
Supplementary 1 Table S1 Minor allele frequencies and age- and centre-adjusted odds ratios for the associations between SNPs in vitamin D-related genes and breast cancer risk among South Asian and Mixed/Other subgroups (DOC 64 kb)
13277_2015_4417_MOESM2_ESM.doc (62 kb)
Supplementary 2 Table S2 Interactions of menopausal status and SNPs in vitamin D-related genes on breast cancer risk in European and East Asian women (DOC 62 kb)
13277_2015_4417_MOESM3_ESM.doc (64 kb)
Supplementary 3 Table S3 Analyses of heterogeneity of odds ratios by ER/PR/HER2-defined tumour subtype for SNPs in vitamin D-related genes among European women (DOC 63 kb)
13277_2015_4417_MOESM4_ESM.doc (64 kb)
Supplementary 4 Table S4 Analyses of heterogeneity of odds ratios by ER/PR/HER2-defined tumour subtype for SNPs in vitamin D-related genes among East Asian women (DOC 63 kb)
13277_2015_4417_MOESM5_ESM.doc (66 kb)
Supplementary 5 Table S5 Analyses of heterogeneity of odds ratios by ER/PR-defined tumour subtype for SNPs in vitamin D-related genes among European and East Asian women (DOC 66 kb)


  1. 1.
    Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian cancer statistics 2014. Toronto: Canadian Cancer Society; 2014.Google Scholar
  2. 2.
    Artaza JN, Sirad F, Ferrini MG, Norris KC. 1,25(OH)2vitamin D3 inhibits cell proliferation by promoting cell cycle arrest without inducing apoptosis and modifies cell morphology of mesenchymal multipotent cells. J Steroid Biochem Mol Biol. 2010;119:73–83.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pilon C, Urbanet R, Williams TA, Maekawa T, Vettore S, Sirianni R, et al. 1α,25-dihydroxyvitamin D3 inhibits the human H295R cell proliferation by cell cycle arrest: a model for a protective role of vitamin D receptor against adrenocortical cancer. J Steroid Biochem Mol Biol. 2014;140:26–33.CrossRefPubMedGoogle Scholar
  4. 4.
    Welsh J. Vitamin D, and breast cancer: insights from animal models. Am J Clin Nutr. 2004;80:1721S–4S.PubMedGoogle Scholar
  5. 5.
    Welsh J. Targets of vitamin D receptor signaling in the mammary gland. J Bone Miner Res. 2007;22:V86–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Mordan-McCombs S, Valrance M, Zinser G, Tenniswood M, Welsh J. Calcium, vitamin D and the vitamin D receptor: impact on prostate and breast cancer in preclinical models. Nutr Rev. 2007;65:S131–3.CrossRefPubMedGoogle Scholar
  7. 7.
    Brosseau C, Pirianov G, Colston KW. Role of insulin-like growth factor binding protein-3 in 1,25-dihydroxyvitamin-D3-induced breast cancer cell apoptosis. Int J Cell Biol. 2013;2013:960378.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Krishnan AV, Swami S, Peng L, Wang J, Moreno J, Feldman D. Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy. Endocrinology. 2010;151:32–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Krishnan AV, Swami S, Feldman D. Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling. J Steroid Biochem Mol Biol. 2010;121:343–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–76.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Matthews D, LaPorta E, Zinser GM, Narvaez CJ, Welsh J. Genomic vitamin D signaling in breast cancer: insights from animal models and human cells. J Steroid Biochem Mol Biol. 2010;121:362–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Anderson LN, Cotterchio M, Kirsh VA, Knight JA. Ultraviolet sunlight exposure during adolescence and adulthood and breast cancer risk: a population-based case–control study among Ontario women. Am J Epidemiol. 2011;174:293–304.CrossRefPubMedGoogle Scholar
  13. 13.
    John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the NHANES I Epidemiologic follow-up study, 1971–1975 to 1992. National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev. 1999;8:399–406.PubMedGoogle Scholar
  14. 14.
    Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat. 2010;121:469–77.CrossRefPubMedGoogle Scholar
  15. 15.
    Abbas S, Linseisen J, Rohrmann S, Chang-Claude J, Peeters PH, Engel P, et al. Dietary intake of vitamin D and calcium and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. Nutr Cancer. 2013;65:178–87.CrossRefPubMedGoogle Scholar
  16. 16.
    Brunner RL, Wactawski-Wende J, Caan BJ, Cochrane BB, Chlebowski RT, Gass MLS, et al. The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women’s Health Initiative (WHI) Calcium Plus Vitamin D randomized clinical trial. Nutr Cancer. 2011;63:827–41.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL. Plasma vitamin D levels, menopause, and risk of breast cancer: dose–response meta-analysis of prospective studies. Medicine. 2013;92:123–31.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wang J, Eliassen AH, Spiegelman D, Willett WC, Hankinson SE. Plasma free 25-hydroxyvitamin D, vitamin D binding protein, and risk of breast cancer in the Nurses’ Health Study II. Cancer Causes Control. 2014;25:819–27.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Garland CF, Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103:708–11.CrossRefPubMedGoogle Scholar
  20. 20.
    Shao T, Klein P, Grossbard ML. Vitamin D and breast cancer. Oncologist. 2012;17:36–45.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim Y, Je Y. Vitamin D intake, blood 25(OH)D levels, and breast cancer risk or mortality: a meta-analysis. Br J Cancer. 2014;110:2772–84.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chlebowski RT. Vitamin D, and breast cancer: interpreting current evidence. Breast Cancer Res. 2011;13:217.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet. 1993;92:183–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Ahn J, Albanes D, Berndt SI, Peters U, Chatterjee N, Freedman ND, et al. Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis. 2009;30:769–76.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sinotte M, Diorio C, Berube S, Pollak M, Brisson J. Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women. Am J Clin Nutr. 2009;89:634–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss EJ, Flesch-Janys D, et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status. Cancer Epidemiol Biomarkers Prev. 2008;17:1339–43.CrossRefPubMedGoogle Scholar
  27. 27.
    Anderson LN, Cotterchio M, Cole DE, Knight JA. Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario. Cancer Epidemiol Biomarkers Prev. 2011;20:1708–17.CrossRefPubMedGoogle Scholar
  28. 28.
    Dorjgochoo T, Delahanty R, Lu W, Long J, Cai Q, Zheng Y, et al. Common genetic variants in the vitamin D pathway including genome-wide associated variants are not associated with breast cancer risk among Chinese women. Cancer Epidemiol Biomarkers Prev. 2011;20:2313–6.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jorde R, Schirmer H, Wilsgaard T, Joakimsen RM, Mathiesen EB, Njølstad I, et al. Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromsø Study. PLoS One. 2012;7:e37295.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    McCullough ML, Stevens VL, Diver WR, Feigelson HS, Rodriguez C, Bostick RM, et al. Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case–control study. Breast Cancer Res. 2007;9:R9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Du Y, Hu L, Kong F, Pan Y. Lack of association between vitamin D receptor gene BsmI polymorphism and breast cancer risk: an updated meta-analysis involving 23,020 subjects. Tumour Biol. 2014;35:2087–93.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang J, He Q, Shao Y, Ji M, Bao W. Associations between vitamin D receptor polymorphisms and breast cancer risk. Tumor Biol. 2013;34:3823–30.CrossRefGoogle Scholar
  33. 33.
    Yang B, Liu S, Yang X, Wang Y, Zhao X, Zheng D, et al. Current evidence on the four polymorphisms of VDR and breast cancer risk in Caucasian women. Meta Gene. 2014;2:41–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Luo S, Guo L, Li Y, Wang S. Vitamin D receptor gene ApaI polymorphism and breast cancer susceptibility: a meta-analysis. Tumor Biol. 2014;35:785–90.Google Scholar
  35. 35.
    Shan J, Dai N, Yang X, Qian C, Yang Z, Jin F, et al. FokI polymorphism in vitamin D receptor gene and risk of breast cancer among Caucasian women. Tumor Biol. 2014;35:3503–8.Google Scholar
  36. 36.
    Wang H, Wang W, Yang D, Wang S. TaqI polymorphism of VDR gene contributes to breast cancer risk. Tumor Biol. 2014;35:93–102.CrossRefGoogle Scholar
  37. 37.
    Uitterlinden AG, Fang Y, van Meurs JBJ, van Leeuwen H, Pols HAP. Vitamin D receptor gene polymorphisms in relation to vitamin D related disease states. J Steroid Biochem Mol Biol. 2004;89:187–93.CrossRefPubMedGoogle Scholar
  38. 38.
    Engel LS, Orlow I, Sima CS, Satagopan J, Mujumdar U, Roy P, et al. Vitamin D receptor gene haplotypes and polymorphisms and risk of breast cancer: a nested case–control study. Cancer Epidemiol Biomarkers Prev. 2012;21:1856–67.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Yao S, Zirpoli G, Bovbjerg DH, Jandorf L, Hong CC, Zhao H, et al. Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case–control study. Breast Cancer Res. 2012;14:R58.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    De Bakker PIW, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D, et al. Efficiency and power in genetic association studies. Nat Genet. 2005;37:1217–23.CrossRefPubMedGoogle Scholar
  41. 41.
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.CrossRefPubMedGoogle Scholar
  42. 42.
    Grundy A, Schuetz JM, Lai AS, Janoo-Gilani R, Leach S, Burstyn I, et al. Shift work, circadian gene variants and risk of breast cancer. Cancer Epidemiol. 2013;37:606–12.CrossRefPubMedGoogle Scholar
  43. 43.
    Rothman KJ, Greenland S, Lash TL. Modern epidemiology. Philadelphia: Lippincott Williams & Wilkins; 2008.Google Scholar
  44. 44.
    Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300.Google Scholar
  45. 45.
    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Reimers LL, Crew KD, Bradshaw PT, Santella RM, Steck SE, Sirosh I, et al. Vitamin D-related gene polymorphisms, plasma 25-hydroxyvitamin D, and breast cancer risk. Cancer Causes Control. 2015;26:187–203.Google Scholar
  47. 47.
    Uitterlinden AG, Fang Y, van Meurs JBJ, Pols HAP, van Leeuwen JPTM. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338:143–56.CrossRefPubMedGoogle Scholar
  48. 48.
    Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol. 2003;86:225–30.CrossRefPubMedGoogle Scholar
  49. 49.
    Abbas S, Nieters A, Linseisen J, Slanger T, Kropp S, Mutschelknauss EJ, et al. Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk. Breast Cancer Res. 2008;10:R31.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    McKay JD, McCullough ML, Ziegler RG, Kraft P, Saltzman BS, Riboli E, et al. Vitamin D receptor polymorphisms and breast cancer risk: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev. 2009;18:297–305.CrossRefPubMedGoogle Scholar
  51. 51.
    Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res. 2009;7:4–13.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287–312.CrossRefPubMedGoogle Scholar
  53. 53.
    Kawase T, Matsuo K, Suzuki T, Hirose K, Hosono S, Watanabe M, et al. Association between vitamin D and calcium intake and breast cancer risk according to menopausal status and receptor status in Japan. Cancer Sci. 2010;101:1234–40.CrossRefPubMedGoogle Scholar
  54. 54.
    Shahbazi S, Alavi S, Majidzadeh-A K, GhaffarPour M, Soleimani A, Mahdian R. BsmI but not FokI polymorphism of VDR gene is contributed in breast cancer. Med Oncol. 2013;30:1–6.CrossRefGoogle Scholar
  55. 55.
    Knight JA, Wong J, Blackmore KM, Raboud JM, Vieth R. Vitamin D association with estradiol and progesterone in young women. Cancer Causes Control. 2010;21:479–83.CrossRefPubMedGoogle Scholar
  56. 56.
    Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ. Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem. 2002;277:18649–57.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Joy Shi
    • 1
  • Anne Grundy
    • 2
  • Harriet Richardson
    • 1
  • Igor Burstyn
    • 3
  • Johanna M. Schuetz
    • 4
  • Caroline A. Lohrisch
    • 5
  • Sandip K. SenGupta
    • 6
  • Agnes S. Lai
    • 7
  • Angela Brooks-Wilson
    • 4
    • 8
  • John J. Spinelli
    • 7
    • 9
  • Kristan J. Aronson
    • 1
    • 10
  1. 1.Department of Public Health Sciences and Cancer Research InstituteQueen’s UniversityKingstonCanada
  2. 2.Alberta Cancer Prevention Legacy Fund, Alberta Health ServicesCalgaryCanada
  3. 3.Department of Environmental and Occupational HealthDrexel UniversityPhiladelphiaUSA
  4. 4.Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer AgencyVancouverCanada
  5. 5.Department of Medical Oncology, British Columbia Cancer AgencyVancouverCanada
  6. 6.Department of Pathology and Molecular MedicineQueen’s UniversityKingstonCanada
  7. 7.Department of Cancer Control Research, British Columbia Cancer AgencyVancouverCanada
  8. 8.Department of Biomedical Physiology and KinesiologySimon Fraser UniversityBurnabyCanada
  9. 9.School of Population and Public Health, University of British ColumbiaVancouverCanada
  10. 10.Division of Cancer Care and Epidemiology, Queen’s Cancer Research InstituteKingstonCanada

Personalised recommendations