Metabolic reaction fluxes as amplifiers and buffers of risk alleles for coronary artery disease
Genome-wide association studies have identified thousands of variants associated with disease risk but the mechanism by which such variants contribute to disease remains largely unknown. Indeed, a major challenge is that variants do not act in isolation but rather in the framework of highly complex biological networks, such as the human metabolic network, which can amplify or buffer the effect of specific risk alleles on disease susceptibility. Here we use genetically predicted reaction fluxes to perform a systematic search for metabolic fluxes acting as buffers or amplifiers of coronary artery disease (CAD) risk alleles. Our analysis identifies 30 risk locus-reaction flux pairs with significant interaction on CAD susceptibility involving 18 individual reaction fluxes and 8 independent risk loci. Notably, many of these reactions are linked to processes with putative roles in the disease such as the metabolism of inflammatory mediators. In summary, this work establishes proof of concept that biochemical reaction fluxes can have non-additive effects with risk alleles and provides novel insights into the interplay between metabolism and genetic variation on disease susceptibility.
Authors
- Emanuele Di Angelantonio (ORCID: https://orcid.org/0000-0001-8776-6719)
- Xilin Jiang (ORCID: https://orcid.org/0000-0001-6773-9182)
- Carles Foguet (ORCID: https://orcid.org/0000-0001-8494-9595)
- Samuel A. Lambert (ORCID: https://orcid.org/0000-0001-8222-008X)
- Elodie Persyn (ORCID: https://orcid.org/0000-0001-9104-1972)
- Scott C. Ritchie (ORCID: https://orcid.org/0000-0002-8454-9548)
- Henry J. Taylor (ORCID: https://orcid.org/0000-0003-2088-5240)
- Chief Ben-Eghan (ORCID: https://orcid.org/0000-0001-7743-5991)
- Michael Inouye (ORCID: https://orcid.org/0000-0001-9413-6520)
- Adam S. Butterworth (ORCID: https://orcid.org/0000-0002-6915-9015)
- Yu Xu (ORCID: https://orcid.org/0009-0000-3888-7119)
- John Danesh
Institutions
- National Institutes of Health (US)
- Harvard University (US)
- Baker Heart and Diabetes Institute (AU)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- British Heart Foundation (GB)
- National Institute for Health and Care Research (GB)
- National Human Genome Research Institute (US)
- Lung Institute (US)
- Cambridge University Health Partners (GB)
- Human Technopole (IT)
- Health Data Research UK (GB)
Publication Details
- Journal
- Molecular Systems Biology
- Published
- 2025-04-02
- DOI
- https://doi.org/10.1038/s44320-025-00097-2
- Primary Topic
- Microbial Metabolic Engineering and Bioproduction
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- British Heart Foundation
- Department of Health and Social Care
- Public Health Agency
- Chief Scientist Office, Scottish Government Health and Social Care Directorate
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- Science and Technology Facilities Council
- Health and Social Care Research and Development Division
- NIHR Cambridge Biomedical Research Centre