CIGARETTES AND AIR POLLUTION SHOW CONVERGENT INTERACTIONS WITH APOE-SEX IN HUMANS AND MICE. (11th November 2018) - Haghani, A
Abstract: Cigarette smoke and air pollution are strong risk factors of Alzheimer's disease and other age-associated chronic diseases. While the main effects of these environmental toxicants are well documented, less is known about their interactions with ApoE alleles and gender. This study investigates the pathways of interactions between of sex, ApoE genotype, and environmental toxicants contribute to aging and disease. We co-related humans phenotypic and genomic data with genome-wide transcriptomic data from male and female Apoe transgenic mice exposed to air pollution. Results from the human cohort show that APOE4, sex and smoking are risk factors for mortality that interact with each other. Further, APOE4 decreases the likelihood of being a long-lived smoker (64%), but only in females. We also find that smoking accelerates cognitive aging, but only in APOE4 homozygous females. To complement our human studies, we applied Weighted Gene Co-Expression Network Analysis to identify gene networks differentially expressed in mice as a function of sex, Apoe, and/or environmental toxins. Principle results from these studies included two gene modules with significant interactions among sex, Apoe and air pollution. The "turquoise" module was enriched with longevity-associated pathways, while the "brown" module contained nervous system-associated signaling pathways. Mouse gene hubs had high overlap with 215 previously-defined polygenic genes for predicting long-lived human survivors. This similarity suggests the shared gene modules may underlie a mechanism for differences in lifespan and cognitive aging. This study emphasizes the role of APOE in male vs. female cognitive aging and mortality differences on responding to environmental toxins.