Single-Nucleotide Polymorphisms in Vitamin D-Related Genes May Modify Vitamin D-Breast Cancer Associations

Cancer Epidemiol Biomarkers Prev. 2017 Dec;26(12):1761-1771. doi: 10.1158/1055-9965.EPI-17-0250. Epub 2017 Oct 25.


Background: We previously observed that high serum 25-hydroxyvitamin D (25(OH)D; >38.0 ng/mL) was inversely associated with breast cancer. Here, we examined effect modification by SNPs in vitamin D-related genes.Methods: The Sister Study enrolled 50,884 U.S. women who had a sister with breast cancer, but who had never had breast cancer themselves. Using a case-cohort design, we compared 1,524 women who developed breast cancer within 5 years to 1,810 randomly selected participants. We estimated ratios of HRs (RHRs) for the 25(OH)D-breast cancer association per copy of the minor allele using Cox proportional hazards models. We considered 82 SNPs in 7 vitamin D-related genes (CYP24A1, CYP27B1, CYP2R1, GC, DHCR7/NADSYN1, RXRA, and VDR). We also tested gene-based interactions with 25(OH)D.Results: The SNP with the smallest interaction P value was rs4328262 in VDR (P = 0.0008); the 25(OH)D HR was 0.92 [95% confidence interval (CI), 0.68-1.24] among those homozygous for the common allele, and the minor allele was estimated to decrease the HR by 33% per copy (RHR = 0.67; 95% CI, 0.53-0.85). Five other VDR SNPs showed evidence of interaction at P < 0.05, as did one SNP in CYP2R1 and one in RXRA As a group, the 82 SNPs showed evidence of multiplicative interaction with 25(OH)D (P = 0.04). In gene-based tests, only VDR showed strong evidence of interaction (P = 0.04).Conclusions: SNPs in vitamin D-related genes may modify the association between serum 25(OH)D and breast cancer.Impact: This work strengthens the evidence for protective effects of vitamin D. Cancer Epidemiol Biomarkers Prev; 26(12); 1761-71. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Alleles
  • Breast Neoplasms / blood
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Case-Control Studies
  • Enzymes / genetics*
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Receptors, Calcitriol / genetics*
  • Retinoid X Receptor alpha / genetics*
  • Siblings
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • Vitamin D / metabolism


  • Enzymes
  • Receptors, Calcitriol
  • Retinoid X Receptor alpha
  • Vitamin D
  • 25-hydroxyvitamin D