ABSTRACT
A significant portion of current medical research is devoted to the pursuit of genetic markers that can be used to identify disease or predict susceptibility to disease. In such a quest many investigators hypothesized that genetic variations that alter signalling pathways involved in atherosclerosis affect susceptibility to coronary artery disease (CAD). Fractalkine (FKN) is a small cytokine involved in monocyte chemotaxis and activation. Two single nucleotide polymorphisms, V249I and T280M, have been identified in the receptor coding sequence of FKN. The polymorphisms alter ligand-receptor affinity and are believed to influence an individual's susceptibility to atherosclerosis. Several investigators have tested the latter hypothesis with inconsistent results. In order to clarify the effect of the two polymorphisms on susceptibility to CAD we performed a meta-analysis, using pooled data retrieved from seven case-control studies. In total, 2000 CAD patients and 2841 subjects without evidence of cardiovascular disease were included in the meta-analysis. The 280M allele was associated with a reduced risk for CAD in the heterozygous state. Consequently, this effect was attributed to the only 280M-containing haplotype: I(249)M(280). The latter haplotype was found to be significantly more frequent in the control population's gene pool. Although we do not believe that the retrieved odds ratios render the T280M polymorphism a candidate genetic marker for clinical applications, we do believe that the above genotype-phenotype interaction is indicative of the strong associations between FKN-induced pathways and CAD.
Subject(s)
Coronary Artery Disease/genetics , Polymorphism, Genetic , Receptors, Chemokine/genetics , Adult , Aged , CX3C Chemokine Receptor 1 , Case-Control Studies , Coronary Artery Disease/immunology , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Heterozygote , Humans , Linkage Disequilibrium , Middle Aged , Odds Ratio , Phenotype , Reproducibility of Results , Risk Assessment , Risk FactorsABSTRACT
Clinical complications of atherosclerosis are major causes of morbidity and mortality in Western societies. Recent evidence suggests that formation of atherosclerotic lesions is an inflammatory process involving multiple molecular pathways. Chemokine-mediated mechanisms are potent regulators of such processes by orchestrating the interactions of inflammatory cellular components of the peripheral blood with cellular components of the arterial wall. The increasing evidence supporting the role of chemokine-pathways in atherosclerosis renders chemokine ligands and their receptors potential therapeutic targets. In the following review, we intend to highlight the special structural and functional features of each chemokine sub-family in respect to their role in atherosclerosis and discuss to what extent such knowledge could be applied in diagnostic, prognostic or therapeutic practices.
