Integrative Model of Metabolomics, Equol and Atherosclerotic cardiovascular disease (IMMEA)

PROJECT SUMMARY This proposal, IMMEA (Integrative Models of Metabolites, Equol and Atherosclerotic cardiovascular disease), aims to (1) determine the association of equol-producing status with ASCVD (atherosclerotic cardiovascular disease) and (2) build models of ASCVD from equol, marine omega-3 fatty acids (OM3), metabolites, and

other factors using Probabilistic Graphical Models (PGMs). To achieve these goals, we will leverage the unique datasets from two case-control studies of ASCVD nested within the Tsuruoka Metabolomics Cohort Study (TMCS) and the Tohoku Medical Megabank Project (TMMP) in Japan. ASCVD mortality in Japan is less

than half of that in the US despite a worse profile of lifetime exposure to many traditional risk factors in Japan. It has decreased continuously for the past five decades despite a noticeable rise in total cholesterol. Studies of migrant Japanese to the US showed a dramatic increase in ASCVD rates, indicating that the low ASCVD

mortality is not due to genetic susceptibility but environmental exposure specific to Japan. Diet is a major environmental determinant of ASCVD. The Japanese diet stands out due to its high soy isoflavones (SIFs) and OM3 consumption. While studies in Japan show that SIFs are cardioprotective, a randomized clinical trial

(RCT) of SIFs in the US failed to show their benefit. We posit that this discrepancy is due to equol producing capability. Equol, a metabolite of SIFs, exhibits the most potent anti-atherosclerotic properties among all SIFs. In Japan, 40-70% of individuals produce equol after SIF consumption, while RCTs of SIFs in the US reported

equol production rates of 20-30%. No previous study has examined the association of equol with ASCVD in Japan. We and others show a significant inverse association of dietary intake of OM3 with ASCVD rates in Japan. Underlying mechanisms linking high dietary intake of OM3 and ASCVD are not fully understood.

Metabolomics has emerged as a tool to decipher biological mechanisms. Metabolomics studies of ASCVD typically rely on statistically independent tests, neglecting higher-order dependencies among variables. PGMs provide a flexible framework for modeling extensive collections of variables with complex interactions, yet

PGMs have not been applied to integrative metabolomics analyses in ASCVD. To bridge these critical gaps, IMMEA will conduct two case-control studies of 1,200 subjects nested within each TMCS and TMMP. Completing this study has the potential to provide profound insight into the biological mechanisms underlying

the benefits of the Japanese diet, with implications for the prevention of ASCVD in the US.