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
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.
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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
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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
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ABSTRACT: A considerable number of studies in epidemiology and biomedicine investigate the etiology of complex diseases by considering (self-identified) race as a relevant variable and focusing on the differences in risk among racial groups in the United States; they extensively draw on a genetic hypothesis-viz. the hypothesis that differences in the risk of complex diseases among racial groups are largely due to genetic differences covarying with genetic ancestry-that appears highly problematic in the light of both current biological evidence and the theory of human genome evolution. Is this reason for dismissing self-identified races? No. An alternative promising use of self-identified races exists, and ironically is suggested by those studies that investigate the etiology of complex diseases without focusing on racial differences. These studies provide a large amount of empirical evidence supporting the primacy of the contribution of non-genetic as opposed to genetic factors to the risk of complex diseases. We show that differences in race-or, better, in racial self-identification-may be critically used as proxies for differences in risk-related exposomes and epigenomes in the context of the United States. Self-identified race is what we need to capture the complexity of the effects of present and past racism on people's health and investigate risk-related external and internal exposures, gene-environment interactions, and epigenetic events. In fact patterns of racial self-identifications on one side, and patterns of risk-related exposomes and epigenomes on the other side, constantly coevolve and tend to match each other. However, there is no guarantee that using self-identified races in epidemiology and biomedical research will be beneficial all things considered: special attention must be paid at balancing positive and negative consequences. Copyright © 2015. Published by Elsevier Ltd.Studies in History and Philosophy of Science Part C Studies in History and Philosophy of Biological and Biomedical Sciences 03/2015; 52. DOI:10.1016/j.shpsc.2015.02.004
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