Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease.
Coronary atherosclerosis is a major cause of death in industrialized countries. Monocytes, which play a key role in atherosclerosis, migrate into the vessel wall, presumably guided by specific chemoattractant and adhesion molecules. A compelling candidate for this role is the chemokine receptor CX3CR1, which is expressed on monocytes and acts as either a chemotactic receptor or an adhesion molecule, depending on whether its ligand, fractalkine, is presented free or membrane bound. A common variant of CX3CR1 was recently identified, encoded by the alleles I249 and M280, which form a common I(249)M(280) haplotype. When CX3CR1 genotypes were analyzed in 151 patients with acute coronary syndromes and in 249 healthy controls, CX3CR1 I249 heterozygosity was associated with a markedly reduced risk of acute coronary events, independent of established acquired coronary risk factors (eg, smoking, diabetes). The adjusted odds ratio for this allele was 0.43 (95% confidence interval, 0.26-0.72; P =.001). Consistent with this, functional analysis of peripheral blood mononuclear cells showed that CX3CR1 I249 heterozygosity was associated with a significant decrease in the number of fractalkine binding sites per cell. The results show that CX3CR1 I249 is an independent genetic risk factor for coronary artery disease and that CX3CR1 may be involved in the pathogenesis of atherosclerotic disease. (Blood. 2001;97:1925-1928)
INSERM U479, Faculté Bichat, Paris, France.
D
D
Moatti
S
S
Faure
F
F
Fumeron
M el-W
Mel-W
Amara
P
P
Seknadji
D H
DH
McDermott
P
P
Debré
M C
MC
Aumont
P M
PM
Murphy
D
D
de Prost
C
C
Combadière
D000208:Acute Disease; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC / Q000502:physiology*; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D016017:Odds Ratio; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015728:Receptors, HIV / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors
D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC; D008565:Membrane Proteins; D018121:Receptors, Cytokine; D015728:Receptors, HIV