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 countr ies, Monocytes, which play a key role in atherosclerosis, migrate into the vessel wall, presumably guided by specific chemoattractant and adhesion mol ecules. A compelling candidate for this role is the chemokine receptor CX3C R1,which is expressed on monocytes and acts as either a chemotactic recepto r 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 I249M 280 haplotype, When CX3CR1 genotypes were analyzed in 151 patients with acu te coronary syndromes and in 249 healthy controls, CX3CR1 I249 heterozygosi ty was associated with a markedly reduced risk of acute coronary events, in dependent of established acquired coronary risk factors leg, smoking, diabe tes). The adjusted odds ratio for this allele was 0.43 (95% confidence inte rval, 0.26-0.72; P =.001). Consistent with this, functional analysis of per ipheral 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 geneti c risk factor for coronary artery disease and that CX3CR1 may be involved i n the pathogenesis of atherosclerotic disease. (Blood, 2001;97: 1925-1928) (C) 2001 by The American Society of Hematology.