Association Between Polymorphism In The Chemokine Receptor CX3CR1 And Coronary Atherosclerosis

Objective:It is now widely accepted that inflammatory pathwaysplay a major role in the pathogenesis of atherosclerosis. Inparticular, monocyte/macrophage accumulation andactivation in the vessel wall appear to be critical events, notonly during the initial phase of plaque formation, but also inchronic lesion progression and during acute complicationssuch as plaque rupture and thrombosis. The molecularmechanisms responsible for monocyte accumulation inplaque are likely to include chemokines and their receptorsbecause these molecules are major regulators of specificleukocyte trafficking. The CX3C chemokine fractalkine (FKN)and its 7–transmembrane domain G-protein–coupledreceptor CX3CR1 are particularly compelling candidates.FKN is a unique chemokine because it exists in both asoluble form and in a membrane-anchored form, for exampleon the surface of interleukin-1–activated and tumor necrosisfactor–activated endothelium. Membrane-bound FKN directlymediates the capture and firm adhesion ofCX3CR1-expressing leukocytes, thus providing a novelpathway for leukocyte activation. Soluble FKN has leukocytechemotactic activity. Recently, we identified commonsingle-nucleotide polymorphisms in the open reading frameof CX3CR1. The polymorphisms are nonsynonymoussubstitutions causing relatively conservative amino acidchanges (V249I and T280M;singleletter amino acid code) inthe CX3CR1 protein. The polymorphisms are in stronglinkage disequilibrium, forming a common. I249 M280haplotype. It is interesting that functional CX3CR1 analysisshowed that FKN binding was reduced in peripheral bloodmononuclear cells (PBMCs) from patients with humanimmunodeficiency virus (HIV) homozygous for the I249M280haplotype. Here we report that allele I249 is associated with areduced risk of acute coronary artery disease as well asaltered CX3CR1 expression and ligand-binding affinity.wefurther test this hypothesis byanalyzing the association ofCX3CR1 polymorphism with angiographically definedatherosclerosis 。Methods:Genotyping of the CX3CR1-V249I polymorphismwas performed in a cohort of 94 yellow individuals whounderwent cardiaccatheterization (n=54 with and n=40without CAD, respectively).Results : The frequencies of the V249I and T280Mpolymorphisms showed no deviation from Hardy-Weinbergequilibrium. However, a statistically significant difference ingenotype frequencies was observed in cases compared withcontrols. The adjusted odds ratios (ORs) associated with thepresence of the M280 (TM 1 MM versus TT genotype) andI249 alleles (VI+II versus VV genotype) were 0.49 (95%confidence interval [CI], 0.27-0.89;P 5 .002) and 0.43 (95%CI, 0.26-0.72;P 5 .001), respectively (Table 2). Thus,thesealleles were associated with a reduced risk of acute coronaryevents. To calculate the OR for each genotype carrying theI249 or M280 allele, we also tested the genotype as a 3-classvariable. The adjusted ORs were 0.47 (95% CI, 0.26-0.88;P<0 .02) and 0.68(95% CI, 0.09-5.45;P <0.7) for the TM andMM genotypes,respectively;they were 0.44 (95% CI,0.26-0.75;P<0.003) and 0.39 (95% CI, 0.13-1.19;P<0.099)for the VI and II genotypes,respectively. As shown recently,the T280M and V249I polymorphismsare in complete linkagedisequilibrium and generate combined genotypes of the 9theoretically possible (Table 3) and only 3 haplotypes(V249T280, I249T280, and I249M280). Indeed, all subjectscarrying allele M280 also carry allele I249, whereas insomesubjects, allele I249 is associated with allele T280. However,when the T280M polymorphism was used in the same logisticequation as the V249I polymorphism, only the effect of theI249 allele remained significant: Adjusted ORs were 0.84(95% CI,1.84-0.39;P<0 .669) and 0.48 (95% CI, 0.92-0.25;P<0.028) for the M280 and I249 alleles, respectively.Therefore, we considered that the protective effect was dueto the I249 allele and performed.Conclusions:CX3CR1 I249 heterozygosity was associatedwith a markedly reduced risk of acute coronaryevents,independent of established acquired coronary riskfactors (eg, smoking, diabetes).The CX3CR1 I249 allele isassociated with decreased risk of CAD. This suggests thatCX3CR1 may be involved in the pathogenesis of CAD.