Most genome-wide association studies (GWAS) have been carried out in European ancestry populations; no risk variants for breast cancer have been identified solely from African ancestry GWAS data. Few GWAS hits have replicated in African ancestry populations. In a nested case-control study of breast cancer in the Black Women's Health Study (1,199 cases/1,948 controls), we evaluated index single-nucleotide polymorphisms (SNP) in 21 loci from GWAS of European or Asian ancestry populations, overall, in subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status (ER+/PR+, n = 336; ER-/PR-, n = 229), and in triple-negative breast cancer (TNBC, N = 81). To evaluate the contribution of genetic factors to population differences in breast cancer subtype, we also examined global percent African ancestry. Index SNPs in five loci were replicated, including three associated with ER-/PR- breast cancer (TERT rs10069690 in 5p15.33, rs704010 in 10q22.3, and rs8170 in 19p13.11): per allele ORs were 1.29 [95% confidence interval (CI) 1.04-1.59], P = 0.02, 1.52 (95% CI 1.12-2.08), P = 0.01, and 1.30 (95% CI 1.01-1.68), P = 0.04, respectively. Stronger associations were observed for TNBC. Furthermore, cases in the highest quintile of percent African ancestry were three times more likely to have TNBC than ER+/PR+ cancer. These findings provide the first confirmation of the TNBC SNP rs8170 in an African ancestry population, and independent confirmation of the TERT ER- SNP. Furthermore, the risk of developing ER- breast cancer, particularly TNBC, increased with increasing proportion of global African ancestry. The findings illustrate the importance of genetic factors in the disproportionately high occurrence of TNBC in African American women.

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