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

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. 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 (, and ). We also tested gene-based interactions with 25(OH)D. The SNP with the smallest interaction value was rs4328262 in ( = 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 SNPs showed evidence of interaction at < 0.05, as did one SNP in and one in As a group, the 82 SNPs showed evidence of multiplicative interaction with 25(OH)D ( = 0.04). In gene-based tests, only showed strong evidence of interaction ( = 0.04). SNPs in vitamin D-related genes may modify the association between serum 25(OH)D and breast cancer. This work strengthens the evidence for protective effects of vitamin D. .