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Beyond CYP2C19: inflammation and angiogenesis gene variants drive clopidogrel resistance in CAD patients

Foddha Hajer1, Aouadi Malek2, Abderrahmane Amani3

  • 1Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, BP N 74, Street Tahar Haddad, 5000, Monastir, Tunisia. hajer.foddha@hotmail.fr.

Inflammation Research : Official Journal of the European Histamine Research Society ... [Et Al.]
|October 30, 2025
PubMed

Insights

Genetic variants in inflammation and angiogenesis pathways significantly impact clopidogrel resistance in coronary artery disease patients. Specific SNPs in CCL5, CCR2, and KDR genes influence treatment response, suggesting new therapeutic targets.

Area of Science:

  • Pharmacogenomics
  • Cardiovascular Medicine
  • Immunology

Background:

  • Clopidogrel resistance is a major clinical issue in coronary artery disease (CAD).
  • While CYP450 gene polymorphisms are known factors, inflammation and angiogenesis pathways are increasingly recognized as critical modulators of platelet reactivity and drug response.
  • Genetic variations within these immuno-vascular pathways may underlie treatment failure in some patients.

Purpose of the Study:

  • To investigate the association between single nucleotide polymorphisms (SNPs) in inflammation-related genes (CCR2, CCL5, CCL2) and angiogenesis-related genes (KDR, VEGFA).
  • To determine if these genetic variants contribute to clopidogrel resistance in patients with coronary artery disease.

Main Methods:

  • A cross-sectional study involving 135 Tunisian CAD patients undergoing dual antiplatelet therapy.
  • Clopidogrel response was assessed using the VerifyNow P2Y12 assay, with resistance defined as a Platelet Reactivity Unit (PRU) score ≥ 208.
  • Nine specific SNPs were genotyped using PCR-RFLP, and associations with clopidogrel resistance were analyzed via logistic regression.

Main Results:

  • The CCL5 rs2280789-C allele was associated with a 3.4-fold increased risk of clopidogrel resistance (p=0.002).
  • The CCR2 rs1799864-A allele showed a protective effect (p=0.02), while the KDR rs1870377-AA genotype increased resistance odds by threefold (p=0.04).
  • A polygenic analysis indicated that carrying two or more risk genotypes (CCR2-GG, CCL5-TC, KDR-AA) significantly increased resistance, affecting 53% of non-responders versus 15% of responders (p<0.001).

Conclusions:

  • Clopidogrel resistance is influenced by immuno-vascular mechanisms beyond CYP450 metabolism, involving genes related to inflammation (CCL5, CCR2) and angiogenesis (KDR/VEGFR2).
  • Genetic variations in CCL5, CCR2, and KDR play a role in modulating platelet reactivity and clopidogrel response.
  • These findings support the development of precision antiplatelet strategies that incorporate genetic profiling of inflammatory and angiogenic pathways to optimize treatment efficacy in CAD patients.
Abstract

Keywords:
AngiogenesisCCL5CCR2Clopidogrel resistanceCoronary artery diseaseGenetic polymorphismInflammationKDRVEGFR

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