Abstract
IntroductionAmerican women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. 25-hydroxyvitamin D (25OHD) is low in AAs, and was associated with ER-negative tumors in EAs. We hypothesized that racial differences in 25OHD levels, as well as in inherited genetic variations, may contribute, in part, to the differences in tumor characteristics.MethodsIn a case (n = 928)-control (n = 843) study of breast cancer in AA and EA women, we measured serum 25OHD levels in controls and tested associations between risk and tag single nucleotide polymorphisms (SNPs) in VDR, CYP24A1 and CYP27B1, particularly by ER status.ResultsMore AAs had severe vitamin D deficiency (< 10 ng/ml) than EAs (34.3% vs 5.9%), with lowest levels among those with the highest African ancestry. Associations for SNPs differed by race. Among AAs, VDR SNP rs2239186, associated with higher serum levels of 25OHD, decreased risk after correction for multiple testing (OR = 0.53, 95% CI = 0.31-0.79, p by permutation = 0.03), but had no effect in EAs. The majority of associations were for ER-negative breast cancer, with seven differential associations between AA and EA women for CYP24A1 (p for interaction < 0.10). SNP rs27622941 was associated with a > twofold increased risk of ER-negative breast cancer among AAs (OR = 2.62, 95% CI = 1.38-4.98), but had no effect in EAs. rs2209314 decreased risk among EAs (OR = 0.38, 95% CI = 0.20-0.73), with no associations in AAs. The increased risk of ER-negative breast cancer in AAs compared to EAs was reduced and became non-significant (OR = 1.20, 95% CI = 0.80-1.79) after adjusting for these two CYP24A1 SNPs.ConclusionsThese data suggest that genetic variants in the vitamin D pathway may be related to the higher prevalence of ER-negative breast cancer in AA women.
Highlights
American women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. 25-hydroxyvitamin D (25OHD) is low in AAs, and was associated with estrogen receptornegative (ER-)negative tumors in EAs
In this study, we found that relationships between breast cancer risk and variants in genes associated with vitamin D activity and metabolism, vitamin D receptor (VDR) and CYP24A1, differed depending upon self-reported race and that associations were most notable for risk of ER- breast cancer in both AA and EA women
Our study provides evidence that variants in vitamin Drelated genes may contribute to higher risk of ER- breast cancer in AA than EA women
Summary
American women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. 25-hydroxyvitamin D (25OHD) is low in AAs, and was associated with ER-negative tumors in EAs. American women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. American women of African ancestry (AA) are more likely to develop breast cancer at a younger age than those with European ancestry (EA) and are more likely to have tumors with aggressive characteristics, including high histological grade, negative estrogen receptor (ER). In high-latitude areas where UVB intensity is low and where more time may be spent indoors ( in winter), vitamin D deficiency may result among individuals with higher skin pigmentation. In the US, the prevalence of 25-hydroxyvitamin D (25OHD) of less than 15 ng/mL is almost 10 times higher in AA than in EA women [8], and the prevalence of severe vitamin D deficiency (< 10 ng/mL) among AAs was 29% in 2001 to 2004 [9]. In Guinea-Bissau, the average 25OHD levels in healthy Africans were 34 ng/mL, and the prevalence of severe vitamin D deficiency was as low as 1% [10]
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