Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome. A possible implication of fractalkine in inflammatory activation.
Several lines of evidence suggest that the chemokine fractalkine (FKN) and its receptor CX3CR1 contribute to the accumulation of leukocytes in the atherosclerotic plaque. The M280 allele of the CX3CR1T280M polymorphism modulates leukocyte recruitment and is associated with lower prevalence of cardiovascular disease. The influence of V249I, another CX3CR1 polymorphism, is discussed controversially. We investigated the association of the alleles M280 and I249 of CX3CR1 with coronary artery disease (CAD) and with acute coronary syndrome (ACS). Additionally, we assessed their association with the soluble ligand FKN and inflammatory activation measured by high sensitivity C-reactive protein (hsCRP). The genotypes of the V249I and T280M polymorphisms were determined in 1152 patients with suspected CAD.720 (62.5%) individuals showed significant CAD with an ACS prevalence of 59.3%. Using multivariate regression, we found a harmful influence of I249 (adjusted OR=1.8, P<0.03) and a protective effect of M280 (adjusted OR=0.6, P<0.04) on the occurrence of ACS in patients with CAD. Correspondingly, patients with I249 but without M280 (17%) were at elevated risk of ACS (OR=1.6, P<0.04). During ACS these patients (carrying only I249) had significantly higher circulating concentrations of FKN and high sensitivity C-reactive protein (1.9- and 1.6-fold). We found no association of the I249 or the M280 allele with the occurrence of CAD. In conclusion, I249 and M280 have opposite effects on the occurrence of ACS. The presence of I249 not "balanced" by M280 confers an elevated risk of ACS. A FKN-mediated enhanced inflammatory activation might explain this increased risk.
Niessner
Alexander
A
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria. alexander.niessner@meduniwien.ac.at
Marculescu
Rodrig
R
Haschemi
Arvand
A
Endler
Georg
G
Zorn
Gerlinde
G
Weyand
Cornelia M
CM
Maurer
Gerald
G
Mannhalter
Christine
C
Wojta
Johann
J
Wagner
Oswald
O
Huber
Kurt
K
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000483:Alleles; D002097:C-Reactive Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002318:Cardiovascular Diseases / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000235:genetics* / Q000378:metabolism; D003062:Codon; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007962:Leukocytes / Q000378:metabolism; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D015995:Prevalence; D019707:Receptors, Chemokine / Q000235:genetics*; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology; D015728:Receptors, HIV / Q000235:genetics / Q000502:physiology; D012306:Risk; D012307:Risk Factors; D012680:Sensitivity and Specificity
D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D002352:Carrier Proteins; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D003062:Codon; D008024:Ligands; D008565:Membrane Proteins; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D002097:C-Reactive Protein