Genetic variants of glucose metabolism and exposure to smoking in African American breast cancer

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.