Discovery of a potential molecular mechanism to reduce cardiovascular risk in 6 genetic regions through the metabolites they regulate

• Researchers from five Catalan research centres have collaborated on a large-scale genetic study in search of new biomarkers and therapeutic pathways.
• They have identified genetic loci and therapeutic targets that could reduce cardiovascular risk by modulating blood metabolites.
• The findings, published in the journal Genome Medicine, open new avenues for assessing and lowering the risk of cardiovascular diseases.

A team of researchers from Girona Biomedical Research Institute Dr. Josep Trueta (IDIBGI), Bellvitge Biomedical Research Institute (IDIBELL), IRB Barcelona, Institut Català d'Oncologia (ICO), Germans Trias i Pujol Research Institute (IGTP) have worked together to identify possible genes associated with certain metabolites - molecules involved in the body's biochemical processes - and cardiovascular risk.

The scientists analysed the levels of 187 such compounds in plasma samples from 4,974 participants in the Catalan GCAT cohort. They integrated this data with other genetic databases from European individuals, reaching a total of 40,000, and re-analysed the data. As a result, they identified 44 genetic regions associated with these metabolites.

To identify how these genetic regions influence metabolites, the findings were combined with gene expression panels from 58 different tissue and cell types. The researchers were able to pinpoint the genes that, through modulation of their expression, are responsible for the levels of these molecules in the body.

This same methodology was applied to data from three European studies involving around 700,000 participants, aiming to study the relationship between gene expression and cardiovascular events, such as heart attacks.

Finally, the researchers explored the causal relationship between gene expression, metabolite levels, and cardiovascular risk through a genetic mediation analysis.

Thanks to these various analyses, the researchers have identified a potential molecular mechanism by which six genetic loci (genetic regions) are associated with cardiovascular risk through the metabolites they regulate. In this way, this study, published in Genome Medicine, a leading journal from the Springer Nature publishing group, highlights new genetic targets with therapeutic potential.

Rafael de Cid, strategic project leader of IGTP's GCAT|Genomes for Life and corresponding author of the study, explains: "These findings not only deepen our understanding of the underlying mechanisms of cardiovascular risk but also suggest new targets for drug development". He adds that "regulating blood metabolite levels by modulating gene expression could offer a new pathway to reduce cardiovascular events in high-risk populations".

Robert Carreras-Torres, researcher at IDIBGI and lead author of the publication, notes: "The paper enables us to identify lipids, such as fats, that act as mediators between the expression of certain genes and cardiovascular risk. As such, it describes a chain of risk factors from genetic predisposition to cardiovascular risk, via gene activation and lipid levels in the blood".

The study underscores the importance of large-scale genetic research for identifying new biomarkers and therapeutic strategies. Identifying key genes associated with metabolites and cardiovascular risk offers the potential to develop personalised treatments, enhancing the prevention and treatment of cardiovascular diseases, which remain one of the leading causes of mortality worldwide.