# Genetic Variation in the Chemokine Network and Atherosclerosis Risk

## TL;DR

This paper reviews how genetic differences in chemokine pathways are linked to atherosclerosis and suggests targeting these pathways could help prevent heart disease.

## Contribution

The paper highlights new genetic evidence supporting chemokine pathways as promising therapeutic targets for reducing atherosclerosis risk.

## Key findings

- Genetic variants in CCL2-CCR2, CXCL12-CXCR4, and CXCL10-CXCR3 chemokine axes are strongly associated with atherosclerotic cardiovascular disease.
- Experimental and clinical data support targeting these pathways to reduce vascular inflammation and stabilize plaques.
- Recent trials show anti-inflammatory agents targeting chemokine pathways may effectively prevent cardiovascular events.

## Abstract

This review examines the impact of genetic variation in chemokines and their receptors on the risk of atherosclerosis and adverse cardiovascular outcomes.

Human genetic studies have identified associations between variants in multiple chemokines and chemokine receptor loci and atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease and myocardial infarction, carotid atherosclerosis and large-artery atherosclerotic stroke, as well as peripheral artery disease. Among chemokine pathways, the most consistent evidence implicates the CCL2-CCR2, CXCL12-CXCR4, and CXCL10-CXCR3 axes. Triangulation with experimental, epidemiological, and human tissue data supports the potential of targeting these pathways to reduce vascular inflammation, promote plaque stabilization, and lower ASCVD risk.

Recent proof-of-concept trials have demonstrated the efficacy of anti-inflammatory therapeutics in atherosclerosis. As the field moves towards a newer generation of atherosclerosis-specific anti-inflammatory agents, human genetic evidence supports targeting chemokine pathways, particularly those governing immune cell trafficking, as a promising therapeutic strategy. These findings provide a strong background for clinical trials assessing anti-chemokine drugs for the prevention of cardiovascular events.

Graphical overview of the role of genetic variation in the chemokine network in prioritization of drug targets for atherosclerotic cardiovascular disease. GWAS – Genome-wide association studies, LoF – Loss of function, ASCVD – atherosclerotic cardiovascular disease. Created in https://BioRender.com.