胰岛素抵抗（IR）是非裔美国女性绝经后患乳腺癌（BC）的已知危险因素。虽然肥胖和IR在非裔美国女性中比白人女性更普遍，但它们在全基因组的IR系统调控研究中却很少被研究。通过检查我们数据中可用的780个全基因组IR单核苷酸多态性（SNP），我们在随机生存森林框架中测试了4,689名非裔美国女性。在考虑到37个与生活方式相关的BC因素的同时，我们进行了基因-环境相互作用分析，以评估最具影响力的遗传和行为因素对BC风险的风险预测，并评估其在BC风险中的组合和联合效应。通过在预测模型中考虑个体SNPs变异，在BC中检测到4个与空腹血糖相关的SNP，分别为PCSK1、SPC25、ADCY5和MTNR1B，以及3个生活方式因素（吸烟、口服避孕药使用和更年期年龄）作为BC风险最具预测性的标记。我们对风险基因型和吸烟的联合分析显示，以基因-生活方式剂量依赖的方式协同作用，增加BC，特别是ER / PR + BC的风险。吸烟的联合效应在长期接触香烟和女性荷尔蒙的女性中更为显著。与代谢生物标志物相关的顶级GWA-SNP与生活方式相结合，可以协同增加非裔美国妇女浸润性ER / PR阳性BC风险的可预测性。我们的研究结果突出了针对具有特定风险基因型和生活方式的妇女的普遍预防干预重点。

Insulin resistance (IR) is a well-established risk factor for breast cancer (BC) development in African American (AA) postmenopausal women. While obesity and IR are more prevalent in AA than white women, they are under-represented in genome-wide studies for systemic regulation of IR. By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in our data, we tested 4,689 AA women in a Random Survival Forest framework. With 37 BC-associated lifestyle factors, we conducted a gene-environment interaction analysis to estimate risk prediction for BC with the most influential genetic and behavioral factors and evaluated their combined and joint effects on BC risk. By accounting for variations of individual SNPs in BC in the prediction model, we detected 4 fasting glucose-associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and 3 lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyle with smoking revealed a synergistic effect on increased risk of BC, particularly ER/PR+ BC, in a gene-lifestyle dose-dependent manner. The joint effect of smoking was more substantial in women with a prolonged exposure to cigarette smoking and female hormones. The top GWA-SNPs associated with metabolic biomarkers in combination with lifestyles synergistically increase the predictability of invasive ER/PR positive BC risk among AA women. Our findings highlight generically targeted preventive interventions for women who carry particular risk genotypes and lifestyles.