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Thromb Haemost 2005; 93(05): 949-954
DOI: 10.1160/TH04-11-0735
Cell Signalling and Vessel Remodelling
Schattauer GmbH

Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome

A possible implication of fractalkine in inflammatory activation
Alexander Niessner   *
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria
,
Rodrig Marculescu   *
2   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
,
Arvand Haschemi
2   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
,
Georg Endler
2   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
,
Gerlinde Zorn
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria
,
Cornelia M. Weyand
3   Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, Georgia, USA
,
Gerald Maurer
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria
,
Christine Mannhalter
2   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
,
Johann Wojta
1   Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria
,
Oswald Wagner
2   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
,
Kurt Huber
4   3rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen-Hospital, Vienna, Austria
› Institutsangaben
Financial support: This study was supported by grants from the Hans und Blanca Moser-Stiftung zur Förderung der Ausbildung von Krebs- und Herzspezialisten and the Österreichische Kardiologische Gesellschaft to Dr. Rodrig Marculescu
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Publikationsverlauf

Received 13. November 2004

Accepted after resubmission 02. Februar 2005

Publikationsdatum:
11. Dezember 2017 (online)

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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 CX3CR1T280M polymorphism modulates leukocyte recruitment and is associated with lower prevalence of cardiovascular disease. The influence of V249I, another CX3CR1 poly-morphism, 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.

Keywords

Chemokine - fractalkine - polymorphism - acute coronary syndrome - C-reactive protein

* Both authors contributed equally to this work.


 

  • References

  • 1 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-74.
    CrossrefPubMedSuche in Google Scholar
  • 2 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-43.
    CrossrefPubMedSuche in Google Scholar
  • 3 Murdoch C, Finn A.. Chemokine receptors and their role in inflammation and infectious diseases. Blood 2000; 95: 3032-43.
    CrossrefPubMedSuche in Google Scholar
  • 4 Reape TJ, Groot PH. Chemokines andatherosclerosis. Atherosclerosis 1999; 147: 213-25.
    CrossrefPubMedSuche in Google Scholar
  • 5 Boring L, Gosling J, Cleary M. et al. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998; 394: 894-7.
    CrossrefPubMedSuche in Google Scholar
  • 6 Gu L, Okada Y, Clinton SK. et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in lowdensity lipoprotein receptor-deficientmice. Mol Cell 1998; 2: 275-81.
    CrossrefPubMedSuche in Google Scholar
  • 7 Boisvert WA, Santiago R, Curtiss LK. et al. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998; 101: 353-63.
    CrossrefPubMedSuche in Google Scholar
  • 8 Szalai C, Duba J, Prohaszka Z. et al. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 –2518 G/G genotype in CAD patients. Atherosclerosis 2001; 158: 233-9.
    CrossrefPubMedSuche in Google Scholar
  • 9 Valdes AM, Wolfe ML, O'Brien EJ. et al. Val64Ile polymorphism in the C-C chemokine receptor 2 is associated with reduced coronary artery calcification. Arterioscler Thromb Vasc Biol 2002; 22: 1924-8.
    CrossrefPubMedSuche in Google Scholar
  • 10 Bazan JF, Bacon KB, Hardiman G. et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 1997; 385: 640-4.
    CrossrefPubMedSuche in Google Scholar
  • 11 Pan Y, Lloyd C, Zhou H. et al. Neurotactin, a membrane- anchored chemokine upregulated in brain inflammation. Nature 1997; 387: 611-7.
    CrossrefPubMedSuche in Google Scholar
  • 12 Imai T, Hieshima K, Haskell C. et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 1997; 91: 521-30.
    CrossrefPubMedSuche in Google Scholar
  • 13 Combadiere C, Salzwedel K, Smith ED. et al. Identification of CX3CR1.Achemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem 1998; 273: 23799-804.
    CrossrefPubMedSuche in Google Scholar
  • 14 Combadiere C, Potteaux S, Gao JL. et al. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 2003; 107: 1009-16.
    CrossrefPubMedSuche in Google Scholar
  • 15 Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J Clin Invest 2003; 111: 333-40.
    CrossrefPubMedSuche in Google Scholar
  • 16 Wong BW, Wong D, McManus BM. Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol 2002; 11: 332-8.
    CrossrefPubMedSuche in Google Scholar
  • 17 Greaves DR, Hakkinen T, Lucas AD. et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activationregulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2001; 21: 923-9.
    CrossrefPubMedSuche in Google Scholar
  • 18 McDermott DH, Halcox JP, Schenke WH. et al. Association between polymorphismin the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001; 89: 401-7.
    CrossrefPubMedSuche in Google Scholar
  • 19 McDermott DH, Fong AM, Yang Q. et al. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest 2003; 111: 1241-50.
    CrossrefPubMedSuche in Google Scholar
  • 20 Moatti D, Faure S, Fumeron F. et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood 2001; 97: 1925-8.
    CrossrefPubMedSuche in Google Scholar
  • 21 Smith Jr SC, Dove JT, Jacobs AK. et al. ACC/AHA guidelines for percutaneous coronary intervention (revisionof the 1993PTCA guidelines)-executive summary: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines (Committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty) endorsed by the Society for Cardiac Angiography and Interventions. Circulation 2001; 103: 3019-41.
    CrossrefPubMedSuche in Google Scholar
  • 22 Braunwald E, Antman EM, Beasley JW. et al. ACC/ AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2000; 36: 970-1062.
    CrossrefPubMedSuche in Google Scholar
  • 23 Rust S, Funke H, Assmann G. Mutagenically separated PCR (MS-PCR): a highly specific one step procedure for easy mutation detection. Nucleic Acids Res 1993; 21: 3623-9.
    CrossrefPubMedSuche in Google Scholar
  • 24 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-89.
    CrossrefPubMedSuche in Google Scholar
  • 25 Stephens M, Donnelly P.. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162-9.
    CrossrefPubMedSuche in Google Scholar
  • 26 Shah PK. Plaque disruption and thrombosis. Potential role of inflammation and infection. Cardiol Clin 1999; 17: 271-81.
    CrossrefPubMedSuche in Google Scholar
  • 27 vander Wal AC, Becker AE, vander Loos CM. et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 36-44.
    CrossrefPubMedSuche in Google Scholar
  • 28 Maseri A. Inflammation, atherosclerosis, and ischemic events – exploring the hidden side of the moon. N Engl J Med 1997; 336: 1014-6.
    CrossrefPubMedSuche in Google Scholar
  • 29 Lind L. Circulating markers of inflammation and atherosclerosis. Atherosclerosis 2003; 169: 203-14.
    CrossrefPubMedSuche in Google Scholar
  • 30 Simon AD, Yazdani S, Wang W. et al. Circulating levels of IL-1beta, a prothrombotic cytokine, are elevated in unstable angina versus stable angina. J Thromb Thrombolysis 2000; 9: 217-22.
    CrossrefPubMedSuche in Google Scholar
  • 31 Schafer A, Schulz C, Eigenthaler M. et al. Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion. Blood 2004; 103: 407-12.
    CrossrefPubMedSuche in Google Scholar
  • 32 Liuzzo G, Biasucci LM, Gallimore JR. et al. The prognostic value of C-reactive protein and serumamyloid a protein in severe unstable angina. N Engl J Med 1994; 331: 417-24.
    CrossrefPubMedSuche in Google Scholar
  • 33 Chandrasekar B, Mummidi S, Perla RP. et al. Fractalkine (CX3CL1) stimulated by NF-kappa B-dependent inflammatory signals induces aortic smoothmuscle cells proliferation through an autocrine pathway. Biochem J 2003; 373: 247-58.
    PubMedSuche in Google Scholar
  • 34 Garton KJ, Gough PJ, Blobel CP. et al. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 2001; 276: 37993-8001.
    PubMedSuche in Google Scholar