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Opposite effects of CX3CR1 receptor polymorphismsV249I andT280Mon the development of acute coronary syndrome A possible implication of fractalkine in inflammatory activation

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH04-11-0735
Issue: 2005: 93/5 (May) pp. 799-1009
Pages: 949-954

Opposite effects of CX3CR1 receptor polymorphismsV249I andT280Mon the development of acute coronary syndrome A possible implication of fractalkine in inflammatory activation

Alexander Niessner 1,*, Rodrig Marculescu 2,*, Arvand Haschemi2 , Georg Endler 2 , Gerlinde Zorn 1 , Cornelia M.Weyand3 , Gerald Maurer 1 , Christine Mannhalter 2 , JohannWojta 1 , OswaldWagner 2 , Kurt Huber 4
1 Department of Internal Medicine II, Division of Cardiology, Medical University ofVienna, Austria 2 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University ofVienna, Austria 3 Department of Medicine, Lowance Center for Hum

Summary

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 CX3CR1T280Mpolymorphismmodulates leukocyte recruitment and is associated with lower prevalence of cardiovascular disease.The influence ofV249I, 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 highsensitivity C-reactive protein (hsCRP). The genotypes of the V249I andT280Mpolymorphisms were determined in 1152 patients with suspected CAD. 720 (62.5%) individuals showed sig- nificant CADwith anACS 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 ofACS.The presence of I249 not“balanced” byM280 confers an elevated risk of ACS.A FKN-mediated enhanced inflammatory activation might explain this increased risk.