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Thromb Haemost 2005; 94(06): 1251-1256
DOI: 10.1160/TH05-06-0417
Wound Healing and Inflammation/Infection
Schattauer GmbH

Fractalkine receptor polymorphisms V249I and T280M as genetic risk factors for restenosis

Alexander Niessner
1   Department of Internal Medicine II, Division of Cardiology
3   Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, Georgia, USA
,
Rodrig Marculescu
2   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
,
Heda Kvakan
1   Department of Internal Medicine II, Division of Cardiology
,
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
,
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
,
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
,
Oswald Wagner
2   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
,
Kurt Huber
4   3 rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen-Hospital, Vienna, Austria
› Author AffiliationsGrant support: The work of Dr. Alexander Niessner was supported by a “Schrödinger” grant from the “Fonds zur Förderung der wissenschaftlichen Forschung”. 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.
Further Information

Publication History

Received 15 June 2005

Accepted after revision 08 August 2005

Publication Date:
07 December 2017 (online)

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Summary

The chemokine fractalkine (FKN) recruits leukocytes into lesions of the arterial wall, which may lead to restenosis after stenting. FKN also regulates proliferation of smooth muscle cells, another mechanism pivotal to neointimal thickening. We assessed the hypothesis that functionally important polymorphisms of the FKN receptor CX3CR1 influence restenosis after coronary stenting. Three hundred and sixty-five patients undergoing coronary stenting were genotyped for the CX3CR1 polymorphisms V249I and T280M. Restenosis occurred in 25% of patients, and recurrent (> 1) restenosis at the target lesion in 8%.The allele I249 was associated with an increased risk of restenosis (adjusted odds ratio 2.4, 95% confidence interval: 1.3–4.2,P = 0.003) and recurrent restenosis (odds ratio 2.7,95% confidence interval:1.3–5.9,P = 0.011).Particularly, patients with I249 lacking the allele M280 were at an elevated risk of restenosis (P = 0.006) and, accordingly, the haplotype containing I249 but not M280 was more frequent in patients with restenosis (P = 0.001). In conclusion, the CX3CR1 I249 allele is associated with an increased risk of restenosis while the CX3CR1 M280 allele might counteract the harmful influence of I249.These findings show the importance of the chemokine FKN and genetic variations of its receptor for restenosis after coronary stenting. Recognition of these inherited risk modifiers may help to individualize treatment of coronary stenosis.

Keywords

Restenosis - stent - chemotaxis - fractalkine - single nucleotide - polymorphism
 

  • References

  • 1 Smith Jr. SC, Dove JT, Jacobs AK. et al ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA 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.
    CrossrefPubMedGoogle Scholar
  • 2 Bonnici F, Keavney B, Collins R. et al Angiotensin converting enzyme insertion or deletion polymorphism and coronary restenosis: meta-analysis of 16 studies. BMJ 2002; 325: 517-20.
    CrossrefPubMedGoogle Scholar
  • 3 Gomma AH, Elrayess MA, Knight CJ. et al The endothelial nitric oxide synthase (Glu298Asp and –786T>C) gene polymorphisms are associated with coronary in-stent restenosis. Eur Heart J 2002; 23: 1955-62.
    CrossrefPubMedGoogle Scholar
  • 4 Kastrati A, Schomig A, Seyfarth M. et al PlA polymorphism of platelet glycoprotein IIIa and risk of restenosis after coronary stent placement. Circulation 1999; 99: 1005-10.
    CrossrefPubMedGoogle Scholar
  • 5 Kastrati A, Koch W, Berger PB. et al Protective role against restenosis from an interleukin-1 receptor antagonist gene polymorphism in patients treated with coronary stenting. J Am Coll Cardiol 2000; 36: 2168-73.
    CrossrefPubMedGoogle Scholar
  • 6 Zee RY, Fernandez-Ortiz A, Macaya C. et al IL-1 cluster genes and occurrence of post-percutaneous transluminal coronary angioplasty restenosis: a prospective, angiography-based evaluation. Atherosclerosis 2003; 171: 259-64.
    CrossrefPubMedGoogle Scholar
  • 7 Hoppmann P, Koch W, Schomig A. et al The 5A/6A polymorphism of the stromelysin-1 gene and restenosis after percutaneous coronary interventions. Eur Heart J 2004; 25: 335-41.
    CrossrefPubMedGoogle Scholar
  • 8 Walter DH, Schachinger V, Elsner M. et al Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the Pl(A2)allele of the platelet glycoprotein IIIa gene. Eur Heart J 2001; 22: 587-95.
    CrossrefPubMedGoogle Scholar
  • 9 Schillinger M, Exner M, Minar E. et al Heme oxygenase-1 genotype and restenosis after balloon angioplasty: a novel vascular protective factor. J Am Coll Cardiol 2004; 43: 950-7.
    CrossrefPubMedGoogle 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.
    CrossrefPubMedGoogle Scholar
  • 11 Pan Y, Lloyd C, Zhou H. et al Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 1997; 387: 611-7.
    CrossrefPubMedGoogle 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.
    CrossrefPubMedGoogle Scholar
  • 13 Combadiere C, Salzwedel K, Smith ED. et al Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem 1998; 273: 23799-804.
    CrossrefPubMedGoogle 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.
    CrossrefPubMedGoogle 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.
    CrossrefPubMedGoogle Scholar
  • 16 Chandrasekar B, Mummidi S, Perla RP. et al Fractalkine (CX3CL1) stimulated by nuclear factor kappaB (NF-kappaB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway. Biochem J 2003; 373: 547-58.
    CrossrefPubMedGoogle Scholar
  • 17 Daoudi M, Lavergne E, Garin A. et al Enhanced adhesive capacities of the naturally occurring Ile249-Met280 variant of the chemokine receptor CX3CR1. J Biol Chem 2004; 279: 19649-57.
    CrossrefPubMedGoogle Scholar
  • 18 Lavergne E, Labreuche J, Daoudi M. et al Adverse Associations Between CX3CR1 Polymorphisms and Risk of Cardiovascular or Cerebrovascular Disease. Arterioscler Thromb Vasc Biol 2005; 25: 847-53.
    CrossrefPubMedGoogle 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.
    CrossrefPubMedGoogle Scholar
  • 20 McDermott DH, Halcox JP, Schenke WH. et al Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001; 89: 401-7.
    CrossrefPubMedGoogle Scholar
  • 21 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.
    CrossrefPubMedGoogle Scholar
  • 22 Niessner A, Marculescu R, Haschemi A. et al Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome. A possible implication of fractalkine in inflammatory activation. Thromb Haemost 2005; 93: 949-54.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 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.
    CrossrefPubMedGoogle Scholar
  • 24 Smith Jr. SC, Blair SN, Bonow RO. et al AHA/ ACC Guidelines for Preventing Heart Attack and Death in Patients With Atherosclerotic Cardiovascular Disease: 2001 update. A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. J Am Coll Cardiol 2001; 38: 1581-3.
    CrossrefPubMedGoogle Scholar
  • 25 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.
    CrossrefPubMedGoogle Scholar
  • 26 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-89.
    CrossrefPubMedGoogle Scholar
  • 27 Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162-9.
    CrossrefPubMedGoogle Scholar
  • 28 Shah PK. Inflammation, neointimal hyperplasia, and restenosis: as the leukocytes roll, the arteries thicken. Circulation 2003; 107: 2175-7.
    CrossrefPubMedGoogle Scholar
  • 29 Welt FG, Tso C, Edelman ER. et al Leukocyte recruitment and expression of chemokines following different forms of vascular injury. Vasc Med 2003; 8: 1-7.
    CrossrefPubMedGoogle Scholar
  • 30 Cipollone F, Marini M, Fazia M. et al Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty. Arterioscler Thromb Vasc Biol 2001; 21: 327-34.
    CrossrefPubMedGoogle Scholar
  • 31 Zeiffer U, Schober A, Lietz M. et al Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines. Circ Res 2004; 94: 776-84.
    CrossrefPubMedGoogle Scholar
  • 32 Lucas AD, Bursill C, Guzik TJ. et al Smooth muscle cells in human atherosclerotic plaques express the fractalkine receptor CX3CR1 and undergo chemotaxis to the CX3C chemokine fractalkine (CX3CL1). Circulation 2003; 108: 2498-504.
    CrossrefPubMedGoogle Scholar
  • 33 Ghilardi G, Biondi ML, Turri O. et al Internal carotid artery occlusive disease and polymorphisms of fractalkine receptor CX3CR1: a genetic risk factor. Stroke 2004; 35: 1276-9.
    CrossrefPubMedGoogle Scholar