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Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and
D H McDermott1, J P Halcox, W H Schenke
1Molecular Signaling Section, Laboratory of Host Defenses of the National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
Insights
The CX3CR1 I249 allele is linked to a lower risk of coronary artery disease (CAD) and better blood vessel function. This genetic variation in CX3CR1 may play a role in how CAD develops.
Area of Science:
- Cardiovascular Science
- Genetics
- Immunology
Background:
- Fractalkine (CX3CL1) and its receptor CX3CR1 are involved in leukocyte adhesion and migration.
- A specific polymorphism in CX3CR1, V249I, influences receptor function.
- This polymorphism has been investigated for its potential role in cardiovascular diseases.
Purpose of the Study:
- To investigate the association between the CX3CR1-V249I polymorphism and coronary artery disease (CAD).
- To evaluate the impact of this polymorphism on endothelial function in patients undergoing cardiac catheterization.
Main Methods:
- Genotyping of the CX3CR1-V249I polymorphism in 339 white individuals (197 with CAD, 142 without).
- Assessment of endothelium-dependent and -independent coronary vasodilation using acetylcholine and sodium nitroprusside, respectively.
- Measurement of coronary vascular resistance (DeltaCVR) as an index of microvascular dilation.
Main Results:
- The CX3CR1 I249 allele was associated with a reduced prevalence of CAD (OR=0.54, P=0.03) and lower CAD severity.
- Individuals with the I249 allele exhibited improved endothelium-dependent vasodilation compared to V249 homozygotes (P=0.02).
- Endothelium-independent vasodilation was similar between genotypes (P=0.45).
Conclusions:
- The CX3CR1 I249 allele is an independent protective factor against CAD.
- This genotype is linked to enhanced endothelial function, specifically endothelium-dependent vasodilation.
- CX3CR1 signaling pathways may be crucial in the pathogenesis of atherosclerotic coronary artery disease.
Abstract:
Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 microg/min) and sodium nitroprusside (20 microg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (DeltaCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P=0.03). Angiographic severity of CAD was also lower in these subjects (P=0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (DeltaCVR during acetylcholine = -46+/-3% versus -36+/-3%, respectively, P=0.02), whereas DeltaCVR with sodium nitroprusside was similar in both groups (-55+/-2% versus -53+/-2%, P=0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis (P=0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.