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. 2018 Jul 11;20(1):70.
doi: 10.1186/s13058-018-0994-y.

Vitamin D, DNA methylation, and breast cancer

Katie M O'Brien  1   2 , Dale P Sandler  3 , Zongli Xu  3 , H Karimi Kinyamu  4 , Jack A Taylor  3 , Clarice R Weinberg  5
Affiliations

Vitamin D, DNA methylation, and breast cancer

Katie M O'Brien et al. Breast Cancer Res. .

Abstract

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 × 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 × 10-8), cg06177555 (SPN; p = 9.8 × 10-8), and cg13243168 (SMARCD2; p = 2.9 × 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.

Keywords: 25-Hydroxyvitamin D; Breast cancer; DNA methylation; Epigenome-wide association study; Vitamin D.

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Conflict of interest statement

Ethics approval and consent to participate

All women provided written informed consent and the study was approved by the institutional review boards of the National Institute of Environmental Health Sciences and the Copernicus Group.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Quantile-quantile plots for vitamin D-related genes. a The association between DNA methylation and 25(OH)D in the subcohort. b The association between DNA methylation-25(OH)D interactions and breast cancer risk in the case-cohort
Fig. 2
Fig. 2
Manhattan plot (a) and quantile-quantile plot (b) for the associations between serum 25(OH)D levels (modeled continuously) and DNA methylation at 423,500 CpG sites among women in the subcohort (n = 1270 non-Hispanic white women). The reference line shows the cut-off for false discovery rate, q = 0.05
Fig. 3
Fig. 3
Diamond plot comparing –log10 p value × sign of coefficient for the estimated association between 25(OH)D and logit(methylation): subcohort (n = 1270, including 46 breast cancer cases) versus other breast cancer cases (n = 1024). The broken lines show critical values for single (vertical and horizontal grid lines) and Fisher’s combined (diagonal lines) p values, based on χ2 tests with 2 (for single) and 4 (for combined) degrees of freedom
See this image and copyright information in PMC

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