Abstract
Molecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized. In this study, we explored the role of pro-inflammatory cytokines such as C-reactive protein (CRP) and interleukin-6 (IL-6) in those pathways at the genome-wide level. With single-nucleotide polymorphisms (SNPs) in the biomarkers and lifestyles together, we further constructed risk profiles to improve predictability for breast cancer. Our earlier genome-wide association gene-environment interaction study used large cohort data from the Women’s Health Initiative Database for Genotypes and Phenotypes Study and identified 88 SNPs associated with CRP and IL-6. For this study, we added an additional 68 SNPs from previous GWA studies, and together with 48 selected lifestyles, evaluated for the association with breast cancer risk via a 2-stage multimodal random survival forest and generalized multifactor dimensionality reduction methods. Overall and in obesity strata (by body mass index, waist, waist-to-hip ratio, exercise, and dietary fat intake), we identified the most predictive genetic and lifestyle variables. Two SNPs (SALL1 rs10521222 and HLA-DQA1 rs9271608) and lifestyles, including alcohol intake, lifetime cumulative exposure to estrogen, and overall and visceral obesity, are the most common and strongest predictive markers for breast cancer across the analyses. The risk profile that combined those variables presented their synergistic effect on the increased breast cancer risk in a gene–lifestyle dose-dependent manner. Our study may contribute to improved predictability for breast cancer and suggest potential interventions for the women with the risk genotypes and lifestyles to reduce their breast cancer risk.
Highlights
Molecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized
We have extended the scope of modeled genetic factors by including 68 additional single-nucleotide polymorphisms (SNPs) in relation to C-reactive protein (CRP) and IL-6 from previous genome-wide association (GWA) studies that focused on European ancestry with independent r eplications[20,21,43,44]
We examined the association of those top GWA-based SNPs with primary invasive breast cancer risk overall and in obesity-related strata in which the SNPs were associated with CRP and IL-6 at genome-wide significance in our earlier GWA study[42]
Summary
Molecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized. The inflammatory cytokines and the genetic markers have demonstrated different associations with breast cancer according to obesity[16,35] and related lifestyle factors such as physical activity and dyslipidemia[36,37,38] Studying how those lifestyle factors modify and interact with gene and phenotype, leading to increased breast cancer susceptibility, may contribute to the understanding of the complex genotype–phenotype pathway and is important to develop a genetically targeted intervention tool for use in primary breast cancer prevention efforts. Using a large-scale postmenopausal women cohort from the Women’s Health Initiative Database for Genotypes and Phenotypes (WHI dbGaP) Study, we previously performed a genome-wide association (GWA) gene–environment (G × E) interaction study for CRP and IL-6 by addressing the pleiotropic effect of those biomarkers on the gene–phenotype relationship; we identified 88 top GWA single-nucleotide polymorphisms (SNPs)[42]. This approach may allow us to elucidate an empirical pathway through which a substantial proportion of the susceptibility of GWA SNPs in CRP and IL-6 influences breast cancer risk through interactions with specific lifestyles (Figure S1)
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