title: Innate immunity pathways and breast cancer Risk in African American and European-American women in the Women's Circle of Health Study (WCHS).
abstract: 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 P0.0012 (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.
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York, USA. Zhihong.gong@roswellpark.org
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Gong
authors.forename: Lei
authors.initials: L
authors.lastname: Quan
authors.forename: Song
authors.initials: S
authors.lastname: Yao
authors.forename: Gary
authors.initials: G
authors.lastname: Zirpoli
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.forename: Michelle
authors.initials: M
authors.lastname: Roberts
authors.forename: Jean-Gabriel
authors.initials: JG
authors.lastname: Coignet
authors.forename: Citadel
authors.initials: C
authors.lastname: Cabasag
authors.forename: Lara
authors.initials: L
authors.lastname: Sucheston
authors.forename: Helena
authors.initials: H
authors.lastname: Hwang
authors.forename: Gregory
authors.initials: G
authors.lastname: Ciupak
authors.forename: Warren
authors.initials: W
authors.lastname: Davis
authors.forename: Karen
authors.initials: K
authors.lastname: Pawlish
authors.forename: Lina
authors.initials: L
authors.lastname: Jandorf
authors.forename: Dana H
authors.initials: DH
authors.lastname: Bovbjerg
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Hong
mesh_terms: D000328:Adult; D044383:Black People; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D017697:Premenopause; D012307:Risk Factors; D044465:White People; D001741:Black or African American