Submitted by sjc313 on Thu, 08/05/2025 - 10:19
Carles Foguet and Michael Inouye, Cardiovascular Epidemiology Unit
Department of Public Health and Primary Care
A major challenge in understanding the contribution of genetic variation to disease risk is the fact that genetic variants can act within complex biological networks, such as the human metabolic network, which can amplify or buffer their effects on disease.
In this study, performed in the UK Biobank and replicated in the All of Us Research Program, we identify 30 instances where biochemical reaction and transport rates (known as metabolic fluxes) interact with coronary artery disease risk alleles, modulating their effect on disease susceptibility. For instance, we find that individuals with high prostaglandin transport capacity have the effect of specific risk variants mapped to the LPA/PLG locus amplified. Conversely, individuals with a high capacity to metabolize fatty acids away from prostaglandin synthesis are protected from the effect of these alleles. Similar interactions between reaction fluxes and risk alleles are identified at the BCAR1, SMARCA4, TGF-β, and EDNRA loci.
Why is this important?
Our findings quantify how metabolic activity interacts with genetic risk, improving our understanding of the interplay between genetics and metabolism and their contribution to cardiovascular disease.
Link to study: Metabolic reaction fluxes as amplifiers and buffers of risk alleles for coronary artery disease | Molecular Systems Biology