Fred Tabung

PhD, MSPH

The Ohio State University

Assistant Professor

PLCO (Learn more about this study)

PLCO-959

Apr 5, 2022

Metabolomic Profiles of Insulinemic Dietary Patterns and Colorectal Cancer Risk: A Consortium of Metabolomics Studies (COMETS) Analysis

Background: Despite improvements in screening and managing pre-cancerous lesions, there has been a concerning increase in sporadic colorectal cancer (CRC) incidence among young adults (<50 years), especially men, and CRC remains a huge public health burden among all population groups. Though etiology is currently unknown, strong birth cohort effects suggest that recent changes in diet may play an important role. We previously developed the empirical hypothesis-oriented dietary index for hyperinsulinemia (EDIH) score based on circulating c-peptide, a marker of β-cell secretory activity. EDIH was derived using a new method, unbiased by existing research and shown to be more robustly associated with CRC than traditional dietary patterns. Our preliminary data indicates that when the combination and balance of foods in the diet prevents sustained hyperinsulinemia, there is an opportunity for CRC prevention. It is not known how the insulinemic potential of the diet influences insulin signaling pathways and whole-body metabolism. Our goal is to identify dietary patterns that can mitigate CRC risk and develop prevention interventions and targeted dietary guidelines for promoting longer, healthier lives. The Steering Committee of the Consortium of Metabolomics Studies (COMETS) in which PLCO is contributing data, previously approved this project for implementation as a COMETS project. The study participants and data described here are restricted to PLCO only.
Specific Aims: 1) To measure the association of EDIH score with CRC risk (overall CRC, colon and rectum) in phenotypically diverse populations within the international Consortium of Metabolomics Studies (COMETS), 2) To identify the metabolomic profile of an insulinemic dietary pattern and measure the association with CRC risk and 3) To determine whether genetic polymorphisms in pro-insulin and c-peptide related genes modify the association of EDIH with CRC risk.
Study Design: The PLCO cohort will contribute data to all three aims. We will calculate the EDIH score from dietary data and extend the previously identified EDIH - CRC risk associations within COMETS with stratification, to understand how these associations differ by age at diagnosis, sex, body weight, metabolic status, and geography. We will then characterize the metabolomic profiles of insulinemic dietary patterns and relate them to CRC risk. Finally, we will determine if insulin-related gene polymorphisms modify our observed associations.
Cancer relevance: Our integrated examination of diet, genetics and whole-body metabolism in relation to CRC risk in diverse global populations will enable us to understand metabolic effects of insulinemic diets and identify subgroups to target with public health messages and interventions. Findings will augment dietary guidance with more detail to maximally impact CRC prevention.

Aim 1. Measure the association of EDIH score with CRC risk (overall CRC, colon and rectum, and right/left-sided tumors) in phenotypically diverse populations within COMETS. Our preliminary data were derived in the U.S. but have not been replicated among phenotypically and geographically diverse populations. We will measure the association of EDIH with CRC risk (primary analysis) and stratify associations by sex, age of CRC onset (<50 vs. ≥50 years), body mass index (BMI), continent, and metabolic health status (secondary analysis). We hypothesize that a hyperinsulinemic diet is associated with higher risk of colon and rectal cancers. Further, associations are stronger for males, younger age, and higher BMI.

Aim 2. Identify the metabolomic profile of an insulinemic dietary pattern and measure the association with CRC risk (overall CRC, colon and rectum). Metabolomics enables measures of whole-body metabolic response to dietary stimuli. We will identify metabolites associated with EDIH score and construct an integrated EDIH metabolite index score representing metabolic potential of an insulinemic diet encompassing not only insulin, but other EDIH-modulated pathways. We will evaluate associations of single metabolites and EDIH metabolite index with CRC risk. We hypothesize that an EDIH metabolite index is associated with CRC risk.

Aim 3. Measure effect modification of the association of EDIH with CRC risk by genetic polymorphisms in insulinemic pathway related genes (overall CRC, colon and rectum). Genetics could inform population subgroups for whom hyperinsulinemic diets may be most harmful, and for whom low insulinemic diets may be most beneficial (i.e., informing precision prevention). We will determine whether a pro-insulin13 and c-peptide14 related polygenic risk score modifies associations of EDIH metabolite index with CRC risk. We hypothesize that polymorphisms in insulin-related genes modify the association of EDIH with CRC.