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

Alexander Niessner; Rodrig Marculescu; Heda Kvakan; Arvand Haschemi; Georg Endler; Cornelia M. Weyand; Gerald Maurer; Christine Mannhalter; Johann Wojta; Oswald Wagner; Kurt Huber

doi:10.1160/TH05-06-0417

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Internal Medicine II, Division of Cardiology

³Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, Georgia, USA

,

Rodrig Marculescu

²Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria

,

Heda Kvakan

¹Department of Internal Medicine II, Division of Cardiology

,

Arvand Haschemi

²Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria

,

Georg Endler

²Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria

,

Cornelia M. Weyand

³Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, Georgia, USA

,

Gerald Maurer

¹Department of Internal Medicine II, Division of Cardiology

,

Christine Mannhalter

²Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria

,

Johann Wojta

¹Department of Internal Medicine II, Division of Cardiology

,

Oswald Wagner

²Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria

,

Kurt Huber

⁴3 rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen-Hospital, Vienna, Austria

› Author Affiliations

Abstract

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

Full Text

References

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
11 Pan Y, Lloyd C, Zhou H. et al Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 1997; 387: 611-7.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
28 Shah PK. Inflammation, neointimal hyperplasia, and restenosis: as the leukocytes roll, the arteries thicken. Circulation 2003; 107: 2175-7.
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.
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.
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.
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.
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.