4.7 Article

Genetic variation in the vitamin D related pathway and breast cancer risk in women of African ancestry in the root consortium

Journal

INTERNATIONAL JOURNAL OF CANCER
Volume 142, Issue 1, Pages 36-43

Publisher

WILEY
DOI: 10.1002/ijc.31038

Keywords

vitamin D; pathway; breast cancer; single-nucleotide polymorphisms; Mendelian randomization; women of African ancestry

Categories

Funding

  1. National Cancer Institute [CA089085, CA142996, CA161032]
  2. Susan G. Komen for the Cure [SAC110026]
  3. American Cancer Society [MRSG-13-063-01-TBG, CRP-10-119-01-CCE]
  4. Ralph and Marion Falk Medical Research Trust
  5. Breast Cancer Research Foundation
  6. Avon Foundation

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The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p=0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p=0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI=1.24-1.91, p(adj)=0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed. What's new? Emerging evidence links vitamin D with protection from breast cancer. Here the authors explored the role of genetic variants in vitamin D-related genes in breast carcinogenesis among women of African descent, a group afflicted with high breast cancer risk and vitamin D deficiency due to dark skin pigmentation. Combining bioinformatics and experimental evidence, they found no evidence to support the association between vitamin D status and breast cancer risk.

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