Genetic ancestry modifies the association between genetic risk variants and breast cancer risk among Hispanic and non-Hispanic white women

Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics and Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA 94158, US.
Carcinogenesis (Impact Factor: 5.33). 04/2013; 34(8). DOI: 10.1093/carcin/bgt110
Source: PubMed


US Hispanic women have lower breast cancer incidence than non-Hispanic white (NHW) women. Genetic factors may contribute to this difference. Breast cancer genome-wide association studies (GWAS) conducted in women of European or Asian descent have identified multiple risk variants. We tested the association between 10 previously reported single nucleotide polymorphisms (SNPs) and risk of breast cancer in a sample of 4697 Hispanic and 3077 NHW women recruited as part of three population-based case-control studies of breast cancer. We used stratified logistic regression analyses to compare the associations with different genetic variants in NHWs and Hispanics classified by their proportion of Indigenous American (IA) ancestry. Five of 10 SNPs were statistically significantly associated with breast cancer risk. Three of the five significant variants (rs17157903-RELN, rs7696175-TLR1, rs13387042-2q35) were associated with risk among Hispanics but not in NHWs. The odds ratio (OR) for the heterozygous at 2q35 was 0.75 (95% CI = 0.50-1.15) for low IA ancestry and 1.38 (1.04-1.82) for high IA ancestry (p interaction 0.02). The ORs for association at RELN were 0.87 (0.59-1.29) and 1.69 (1.04-2.73), respectively (p interaction 0.03). At the TLR1 locus the ORs for women homozygous for the rare allele were 0.74 (0.42-1.31) and 1.73 (1.19-2.52) (p interaction 0.03). Our results suggest that the proportion of IA ancestry modifies the magnitude and direction of the association of three of the ten previously reported variants. Genetic ancestry should be considered when assessing risk in women of mixed descent and in studies designed to discover causal mutations.

15 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Growth factors (GF) stimulate cell proliferation through binding to cell membrane receptors and are thought to be involved in cancer risk and survival. We examined how genetic variation in epidermal growth factor (EGF), neuregulin 2 (NRG2), ERBB2 (HER2/neu), fibroblast growth factors 1 and 2 (FGF1 and FGF2) and its receptor 2 (FGFR2), and platelet-derived growth factor B (PDGFB) independently and collectively influence breast cancer risk and survival. We analyzed data from the Breast Cancer Health Disparities Study which includes Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,586 controls) women. Adaptive rank-truncated product (ARTP) analysis was conducted to determine gene significance. Odds ratios (OR) and 95 % confidence intervals were obtained from conditional logistic regression models to estimate breast cancer risk and Cox proportional hazard models were used to estimate hazard ratios (HR) of dying from breast cancer. We assessed Native American (NA) ancestry using 104 ancestry informative markers. We observed few significant associations with breast cancer risk overall or by menopausal status other than for FGFR2 rs2981582. This SNP was significantly associated with ER+/PR+ (OR 1.66, 95 % CI 1.37-2.00) and ER+/PR- (OR 1.54, 95 % CI 1.03-2.31) tumors. Multiple SNPs in FGF1, FGF2, and NRG2 significantly interacted with multiple SNPs in EGFR, ERBB2, FGFR2, and PDGFB, suggesting that breast cancer risk is dependent on the collective effects of genetic variants in other GFs. Both FGF1 and ERBB2 significantly influenced overall survival, especially among women with low levels of NA ancestry (P ARTP = 0.007 and 0.003, respectively). Our findings suggest that genetic variants in growth factors signaling appear to influence breast cancer risk through their combined effects. Genetic variation in ERBB2 and FGF1 appear to be associated with survival after diagnosis with breast cancer.
    Breast Cancer Research and Treatment 08/2013; 140(3). DOI:10.1007/s10549-013-2644-5 · 3.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor necrosis factor-α (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast cancer risk among women with >70% NA ancestry (PARTP = 0.0008), with TLR1 rs7696175 being the primary risk contributor (OR 1.77, 95% CI 1.25, 2.51). Overall, TLR1 rs7696175 (HR 1.40, 95% CI 1.03, 1.91; Padj = 0.032), TLR4 rs5030728 (HR 1.96, 95% CI 1.30, 2.95; Padj = 0.014), and TNFRSF1A rs4149578 (HR 2.71, 95% CI 1.28, 5.76; Padj = 0.029) were associated with increased breast cancer mortality. We observed several statistically significant interactions after adjustment for multiple comparisons, including interactions between our dietary oxidative balance score and CD40LG and TNFSF1A; between cigarette smoking and TLR1, TLR4, and TNF; between body mass index (BMI) among pre-menopausal women and TRAF2; and between regular use of aspirin/non-steroidal anti-inflammatory drugs and TLR3 and TRA2. In conclusion, our findings support a contributing role of certain TNF-α and TLR genes in both breast cancer risk and survival, particularly among women with higher NA ancestry. Diet and lifestyle factors appear to be important mediators of the breast cancer risk associated with these genes.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2014; 770. DOI:10.1016/j.mrfmmm.2014.08.009 · 3.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine whether there were differential quit rates between African Americans (AA) and European Americans with the experimental treatment naltrexone, and examine the role of genetic ancestry on these outcomes among AAs. Data from a previous randomized trial of 315 smokers to naltrexone versus placebo were reanalyzed using West African (WA) genetic ancestry to define subpopulations. Logistic regression models were used to estimate treatment effects on early and end of treatment quit rates, by race and WA ancestry. Among European Americans (n=136), naltrexone significantly increased quit rates at 4 weeks (62 vs. 43%, P=0.03) with directional, but not statistically significant effects at 12 weeks (30 vs. 18%, P=0.12). In contrast, among the AAs (n=95), quit rates did not differ between naltrexone and placebo groups at either interval (4 weeks: 43 vs. 32%, P=0.27; 12 weeks: 22 vs. 18%, P=0.60). A median split was conducted in AAs for WA ancestry. Among AAs with low WA ancestry, quit rates were significantly higher with naltrexone compared with placebo (60 vs. 27%, P=0.03). There was no advantage in quit rates with naltrexone for the high WA ancestry group. Naltrexone efficacy for smoking cessation varies across AA individuals with different levels of WA ancestry. These results suggest that genetic background may partially explain racial differences in drug response.
    Pharmacogenetics and Genomics 06/2015; 25(6):305-312. DOI:10.1097/FPC.0000000000000138 · 3.48 Impact Factor