Although the incidence of breast cancer is highest in American women of European ancestry (EA), women of African ancestry (AA) are more likely to have early, aggressive breast cancer, characterized by negative estrogen receptor (ER) status. There are few explanations for these differences between ancestral groups. We hypothesized that differential distribution of genetic variants in innate immunity pathways could be related to these breast cancer disparities, and evaluated variant-breast cancer associations in a case-control study, the Women's Circle of Health Study (WCHS). In the first stage, 44 SNPs were genotyped among 1010 AA and 757 EA women who participated in the WCHS. For 38 of the 44 SNPs, genotype frequencies differed significantly between AA and EA women, and differential risk relationships were observed between groups for some SNPs. For example, in premenopausal women, CXCL5 (rs425535) was significantly associated with breast cancer risk for only AA women (P=0.008) and for EAs, associations were observed for CRP (rs1205) and TNFA (rs1799724) (P≤0.01). In post-menopausal women, two SNPs in IL1B (rs1143627, rs16944) and one SNP in NOD2 (rs2066842) were associated with risk in EAs (all P=0.01) but not AA women. The association was limited to ER positive cancers for TNFA-rs1799724 and to ER negative cancers for NOD2-rs2066842. In the second stage, with additional accruals in WCHS, we extended analysis for four SNPs with suggested associations from the first stage in a larger dataset of 1602 AA and 1542 EA women, which yielded similar results. Associations for CRP-rs1205 and CXCL5-rs425535 with breast cancer risk were strengthened in premenopausal women and were statistically different between AA and EA women (P for interaction=0.0009 and 0.002, respectively) in this larger dataset. In summary, AA and EA populations exhibited differential association patterns of these genetic variants with breast cancer risk. Our findings suggest that innate immune pathways may be differentially associated with breast cancer by ancestry, and that relationships vary according to menopausal and ER status.

Citation Format: Zhihong Gong, Lei Quan, Song Yao, Gary Zirpoli, Elisa Bandera, Helena Hwang, Michelle Roberts, Lara Sucheston, Gregory Ciupak, Warren Davis, Christine Ambrosone, Chi-Chen Hong. Innate Immunity Pathways and Breast Cancer Risk in African American and European American Women in the Women's Circle of Health Study (WCHS). [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 17.