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Background: Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation.

Methods: We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH) D) and methylation within a random sample of the cohort ("subcohort"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH) D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH) D and DNA methylation in the subcohort.

Results: Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH) D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH) D (p < 0.05; RXRA, NADSYN1/DHCR7, GC, or CYP27B1). We observed an interaction between 25(OH) D and methylation at cg21201924 in relation to breast cancer risk (ratio of hazard ratios = 1.22, 95% confidence interval 1.10-1.34; p = 7 x 10(-5)), indicating a larger methylation-breast cancer hazard ratio in those with high serum 25(OH) D concentrations. We also observed statistically significant (p < 0.05) interactions for six other RXRA CpGs and CpGs in CYP24A1, CYP27B1, NADSYN1/DHCR7, and VDR. In the EWAS of the subcohort, 25(OH) D was associated (q < 0.05) with methylation at cg24350360 (EPHX1; p = 3.4 x 10(-8)), cg06177555 (SPN; p = 9.8 x 10(-8)), and cg13243168 (SMARCD2; p = 2.9 x 10(-7)).

Conclusions: 25(OH) D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH) D to affect the risk of breast cancer.