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African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women’s Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with  CXCL5 -rs425535 (OR=0.61,  P =0.02), while among EA women, there were associations with  TNFA -rs1799724 (OR =2.31,  P  =0.002) and  CRP -rs1205 (OR=0.54,  P =0.01). For postmenopausal women,  IL1B- rs1143627 (OR=1.80,  P =0.02) and  IL1B- rs16944 (OR=1.85,  P  =0.02) were associated with risk among EA women, with significant associations for  TNFA -rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0,  P  =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of  P 0.0012 (0.05/42) except for  TNFA -rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs ( CCL2 -rs4586,  CRP -rs1205,  CXCL5 -rs425535, and  IL1RN -rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.

Innate Immunity Pathways and Breast Cancer Risk in African American and European-American Women in the Women’s Circle of Health Study (WCHS)