Genetic Signatures of Glucose Homeostasis: Synergistic Interplay With Long-Term Exposure to Cigarette Smoking in Development of Primary Colorectal Cancer Among African American Women

Insulin resistance (IR)/glucose intolerance is a critical biologic mechanism for the development of colorectal cancer (CRC) in postmenopausal women. Whereas IR and excessive adiposity are more prevalent in African American (AA) women than in White women, AA women are underrepresented in genome-wide studies for systemic regulation of IR and the association with CRC risk. METHODS: With 780 genome-wide IR single-nucleotide polymorphisms (SNPs) among 4,692 AA women, we tested for a causal inference between genetically elevated IR and CRC risk. Furthermore, by incorporating CRC-associated lifestyle factors, we established a prediction model on the basis of gene–environment interactions to generate risk profiles for CRC with the most influential genetic and lifestyle factors. RESUTLS: In the pooled Mendelian randomization analysis, the genetically elevated IR was associated with 9 times increased risk of CRC, but with lack of analytic power. By addressing the variation of individual SNPs in CRC in the prediction model, we detected 4 fasting glucose–specific SNPs in GCK, PCSK1, and MTNR1B and 4 lifestyles, including smoking, aging, prolonged lifetime exposure to endogenous estrogen, and high fat intake, as the most predictive markers of CRC risk. Our joint test for those risk genotypes and lifestyles with smoking revealed the synergistically increased CRC risk, more substantially in women with longer-term exposure to cigarette smoking. DISCUSSION: Our findings may improve CRC prediction ability among medically underrepresented AA women and highlight genetically informed preventive interventions (e.g., smoking cessation; CRC screening to longer-term smokers) for those women at high risk with risk genotypes and behavioral patterns.