Circulation Research. 2001;89:401-407
Published online before print August 16, 2001, doi: 10.1161/hh1701.095642
Published online before print August 16, 2001, doi: 10.1161/hh1701.095642
© 2001 American Heart Association, Inc.
Clinical Research |
Association Between Polymorphism in the Chemokine Receptor CX3CR1 and Coronary Vascular Endothelial Dysfunction and Atherosclerosis
From the Molecular Signaling Section, Laboratory of Host Defenses of the National Institute of Allergy and Infectious Diseases (D.H.M., M.N.M, P.M.M.) and the Cardiology Branch (J.P.J.H., W.H.S., N.E., A.A.Q.) and the Office of Biostatistics Research (M.A.W.) of the National Heart, Lung, and Blood Institute, NIH, Bethesda, Md.
Correspondence to Dr Philip M. Murphy, Bldg 10, Room 11N113, NIH, Bethesda, MD 20892. E-mail pmm{at}nih.gov
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 µg/min) and sodium nitroprusside (20 µg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (
CVR) 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 (CVR during acetylcholine = -46±3% versus -36±3%, respectively, P=0.02), whereas CVR 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.
Key Words: genetics • fractalkine • acetylcholine • inflammation • epidemiology
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