Genetic variations in vitamin D-related pathways and breast cancer risk in African American women in the AMBER consortium

Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p0.05, particularly for ER- breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER- cancer (pathway-level p=0.02), driven by a single gene CASR (gene-level p=0.001). The top SNP in CASR was rs112594756 (p=7 x 10(-5), gene-wide corrected p=0.01), followed by a second signal from a nearby SNP rs6799828 (p=1 x 10(-4), corrected p=0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes. What's new? Vitamin D displays many anti-cancer activities. While African Americans are known to have a high prevalence of vitamin D deficiency, studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry. This study is the largest and most comprehensive investigation of vitamin D-related genetic variations with breast cancer risk and tumor estrogen receptor status in African American women. The data reveal modest associations of genetic variations in vitamin D pathways with breast cancer risk, and suggest a role for vitamin D in risk of estrogen receptor negative breast cancer.