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Background <p>Clopidogrel resistance remains a significant clinical challenge in coronary artery disease (CAD), with traditional explanations focusing on CYP450 polymorphisms. However, emerging evidence highlights the critical role of inflammation and angiogenesis in modulating platelet reactivity and clopidogrel responsiveness. Genetic variants in these pathways may represent under recognized determinants of treatment failure. This pilot study investigated the association between single nucleotide polymorphisms (SNPs) in inflammation- (<i>CCR2</i>, <i>CCL5</i>, <i>CCL2</i>) and angiogenesis-related (<i>KDR</i>, <i>VEGFA</i>) genes and clopidogrel resistance.</p> Methods <p>In a cross-sectional study of 135 Tunisian CAD patients on dual antiplatelet therapy, clopidogrel response was assessed using VerifyNow P2Y12 assay (resistance defined as PRU&#xa0; ≥&#xa0; 208). Nine SNPs were genotyped via PCR–RFLP. Associations were evaluated using logistic regression, adjusting for covariates. </p> Results <p>The <i>CCL5</i> rs2280789-C allele conferred a 3.4-fold increased resistance risk (OR = 3.40 (1.54–7.48), <i>p</i>&#xa0;=&#xa0; 0.002), while the <i>CCR2</i> rs1799864-A allele was protective (OR&#xa0;=&#xa0; 0.30 (0.10–0.84), <i>p</i>&#xa0;=&#xa0; 0.02). The <i>KDR</i> rs1870377-AA genotype tripled resistance odds (OR&#xa0;=&#xa0; 3.05&#xa0;(1.05–8.83), <i>p</i>&#xa0;=&#xa0; 0.04). A polygenic model revealed synergistic effects: 53% of non-responders carried &#xa0;≥&#xa0;2 risk genotypes (<i>CCR2</i>-GG, <i>CCL5</i>-TC, <i>KDR</i>-AA) vs. 15% of responders (OR = 6.51 (2.86–14.83), <i>p</i> &lt; 0.001). No associations were found for <i>VEGFA</i> or <i>CCL2</i> SNPs.</p> Conclusion <p>Beyond CYP450-mediated metabolism, clopidogrel resistance is driven by immuno-vascular mechanisms involving <i>CCL5</i>-mediated thrombo-inflammation, <i>CCR2</i>-dependent monocyte recruitment, and <i>VEGFR2</i>-linked endothelial dysfunction. These findings advocate for precision antiplatelet strategies integrating inflammatory and angiogenic pathways to optimize therapy.</p>

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

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Foddha hajer,
  • Aouadi malek,
  • Abderrahmane Amani,
  • Omrani rahma,
  • Ben Hamda Khaldoun,
  • Foddha Abdelhak,
  • Omezzine Asma,
  • Haj Khelil amel,
  • Chouchene Saoussen

摘要

Background

Clopidogrel resistance remains a significant clinical challenge in coronary artery disease (CAD), with traditional explanations focusing on CYP450 polymorphisms. However, emerging evidence highlights the critical role of inflammation and angiogenesis in modulating platelet reactivity and clopidogrel responsiveness. Genetic variants in these pathways may represent under recognized determinants of treatment failure. This pilot study investigated the association between single nucleotide polymorphisms (SNPs) in inflammation- (CCR2, CCL5, CCL2) and angiogenesis-related (KDR, VEGFA) genes and clopidogrel resistance.

Methods

In a cross-sectional study of 135 Tunisian CAD patients on dual antiplatelet therapy, clopidogrel response was assessed using VerifyNow P2Y12 assay (resistance defined as PRU  ≥  208). Nine SNPs were genotyped via PCR–RFLP. Associations were evaluated using logistic regression, adjusting for covariates.

Results

The CCL5 rs2280789-C allele conferred a 3.4-fold increased resistance risk (OR = 3.40 (1.54–7.48), p =  0.002), while the CCR2 rs1799864-A allele was protective (OR =  0.30 (0.10–0.84), p =  0.02). The KDR rs1870377-AA genotype tripled resistance odds (OR =  3.05 (1.05–8.83), p =  0.04). A polygenic model revealed synergistic effects: 53% of non-responders carried  ≥ 2 risk genotypes (CCR2-GG, CCL5-TC, KDR-AA) vs. 15% of responders (OR = 6.51 (2.86–14.83), p < 0.001). No associations were found for VEGFA or CCL2 SNPs.

Conclusion

Beyond CYP450-mediated metabolism, clopidogrel resistance is driven by immuno-vascular mechanisms involving CCL5-mediated thrombo-inflammation, CCR2-dependent monocyte recruitment, and VEGFR2-linked endothelial dysfunction. These findings advocate for precision antiplatelet strategies integrating inflammatory and angiogenic pathways to optimize therapy.