Genetic variants in one-carbon metabolism genes and breast cancer risk in European American and African American women

Folate-mediated one-carbon metabolism plays critical roles in DNA synthesis, repair and DNA methylation. The impact of single nucleotide polymorphisms (SNPs) in folate-metabolizing enzymes has been investigated in risk of breast cancer among European or Asian populations, but not among women of African ancestry. We conducted a comprehensive analysis of SNPs in eleven genes involved in one-carbon metabolism and risk of breast cancer in 1,275 European-American (EA) and 1,299 African-American (AA) women who participated in the Women's Circle of Health Study. Allele frequencies varied significantly between EA and AA populations. A number of these SNPs, specifically in genes including MTR, MTRR, SHMT1, TYMS and SLC19A1, were associated with overall breast cancer risk, as well as risk by estrogen receptor (ER) status, in either EA or AA women. Associations appeared to be modified by dietary folate intake. Although single-SNP associations were not statistically significant after correcting for multiple comparisons, polygenetic score analyses revealed significant associations with breast cancer risk. Per unit increase of the risk score was associated with a modest 19 to 50% increase in risk of breast cancer overall, ER positive or ER negative cancer (all p<0.0005) in EAs or AAs. In summary, our data suggest that one-carbon metabolizing gene polymorphisms could play a role in breast cancer and that may differ between EA and AA women. What's new? One-carbon metabolic pathways are crucial to DNA methylation and DNA synthesis and provide links between genetic and environmental factors, particularly dietary intake of folate, a major activator of one-carbon units. Folate intake may be inversely associated with breast cancer risk, and genetic variations that affect folate-mediated one-carbon metabolism may modify breast cancer risk. This analysis of SNPs in 11 genes involved in one-carbon metabolic pathways uncovers significant differences in allele frequencies between American women of African and European ancestry. Multiple SNPs were associated with breast cancer risk in the two populations, with suggestions of modification by dietary folate intake.