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Background: We previously observed that high serum 25-hydroxyvitamin D (25(OH)D; &gt;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 &lt; 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 .

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