Genetic, metabolomic, and lifestyle dynamics in colorectal cancer and chronic disease prevention

Abstract

Abstract Noncommunicable chronic disease is a group of conditions that includes type 2 diabetes, cardiovascular disease, and cancer, and accounts for the majority of total deaths in the United States. Many of these diseases are associated with overweight and obese body mass index, however, the pathways linking genetics, modifiable factors, and physiologic characteristics such as inflammation and insulin resistance to chronic disease development are not well understood. A more nuanced understanding of how excess adiposity and related risk factors influence chronic disease is needed to develop improved prevention strategies. We leveraged data from three prospective cohort studies, the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study, to explore these risk factors in relation to chronic disease. In Chapter 1, we evaluated the association of genetically predicted BMI with different colorectal cancer precursor lesions: conventional adenomas and serrated polyps. We found similar associations between measured or genetic BMI and colorectal cancer precursors and observed a stronger association of both measured and genetic BMI with serrated polyps and synchronous serrated polyp and conventional adenoma, compared to conventional adenoma alone. In Chapter 2, we developed metabolomic signatures of inflammation and metabolic disturbance and evaluated the association of the signatures with colorectal cancer. We found that both signatures predicted colorectal cancer risk among men, but not women, and we identified promising individual metabolites linking the states of inflammation and metabolic dysregulation to colorectal cancer development. In Chapter 3, we estimated the proportion and number of cases of chronic disease attributable to poor quality diet and inadequate physical activity in the United States, accounting for the effects of these risk factors that is mediated by changes in body weight. We found that 18 percent of chronic disease in 2018 was attributable to poor quality diet and physical activity, with 13 percent not mediated by effects on change in body weight.