Interleukin-1 cluster combined genotype and restenosis after balloon angioplasty

Rodrig Marculescu; Wolfgang Mlekusch; Markus Exner; Schila Sabeti; Stefanie Michor; Helmut Rumpold; Christine Mannhalter; Erich Minar; Oswald Wagner; Martin Schillinger

doi:10.1160/TH03-01-0064

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(03): 491-500
DOI: 10.1160/TH03-01-0064

Wound Healing and Inflammation/Infection

Schattauer GmbH

Interleukin-1 cluster combined genotype and restenosis after balloon angioplasty

Authors

Rodrig Marculescu

¹Departments of Medical and Chemical laboratory Diagnostics, University of Vienna, Medical School, Austria
Wolfgang Mlekusch

²Departments of Angiology, University of Vienna, Medical School, Austria
Markus Exner

¹Departments of Medical and Chemical laboratory Diagnostics, University of Vienna, Medical School, Austria
Schila Sabeti

²Departments of Angiology, University of Vienna, Medical School, Austria
Stefanie Michor

¹Departments of Medical and Chemical laboratory Diagnostics, University of Vienna, Medical School, Austria
Helmut Rumpold

¹Departments of Medical and Chemical laboratory Diagnostics, University of Vienna, Medical School, Austria
Christine Mannhalter

¹Departments of Medical and Chemical laboratory Diagnostics, University of Vienna, Medical School, Austria
Erich Minar

²Departments of Angiology, University of Vienna, Medical School, Austria
Oswald Wagner

¹Departments of Medical and Chemical laboratory Diagnostics, University of Vienna, Medical School, Austria
Martin Schillinger

²Departments of Angiology, University of Vienna, Medical School, Austria

Abstract

Summary

The interleukin-1 system is fundamentally involved in the pathogenesis of restenosis after percutaneous transluminal angioplasty (PTA). In order to further define the clinical impact of genetic variation in this potent proinflammatory pathway we investigated the joint effects of two single nucleotide polymorphisms in the interleukin-1 beta gene [IL-1B(–511) and IL-1B(+3954)] and a variable number tandem repeat polymorphism in intron 2 of the interleukin 1 receptor antagonist gene (IL-1RN VNTR) on postintervention inflammation and occurrence of restenosis in 183 consecutive patients who underwent successful femoropopliteal PTA. C-reactive protein (CRP) and serum amyloid A (SAA) were determined pre- and 48 hours postintervention. Patients were followed up to 12 months for the occurrence of postangioplasty restenosis (≥50 %). When analyzed separately, none of the polymorphisms was associated either with inflammation or restenosis. However, when the IL-1B (–511) and the IL-1RN VNTR genotypes were combined, a highly significant relationship was observed: Non-carriers of the two repeat allele of the IL-1RN VNTR (IL-1RN*2) who were heterozygous and homozygous for the IL-1B (–511)T allele exhibited a gradually increased inflammatory response and a higher restenosis risk. In contrast, carriers of the IL-1RN*2 and the IL-1B (–511)T allele showed a significantly better outcome.

This remarkable gene dose-dependent association emphasizes the advantage of considering combinations of genetic markers rather that isolated polymorphisms in the analysis of multifactorial vascular disease.

Keywords

Atherosclerosis - restenosis - cytokines - gene mutations

Full Text

References

References
1 Schillinger M, Haumer M, Schlerka G. et al. Restenosis after percutaneous transluminal angioplasty in the femoropopliteal segment: the role of inflammation. J Endovasc Ther 2001; 8 (05) 477-83.
2 Schillinger M, Exner M, Mlekusch W. et al. Vascular inflammation and percutaneous transluminal angioplasty of the femoropopliteal artery: association with restenosis. Radiology 2002; 225 (01) 21-6.
3 Orford JL, Selwyn AP, Ganz P, Popma JJ, Rogers C. The comparative pathobiology of atherosclerosis and restenosis. Am J Cardiol 2000; 86 4B 6H-11H.
4 Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340 (02) 115-26.
5 Liuzzo G, Buffon A, Biasucci LM. et al. Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina. Circulation 1998; 98 (22) 2370-6.
6 Gottsauner-Wolf M, Zasmeta G, Hornykewycz S. et al. Plasma levels of C-reactive protein after coronary stent implantation. Eur Heart J 2000; 21 (14) 1152-8.
7 Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol 1999; 10 (06) 499-506.
8 Farb A, Sangiorgi G, Carter AJ. et al. Pathology of acute and chronic coronary stenting in humans. Circulation 1999; 99 (01) 44-52.
9 Ikeda U, Ikeda M, Oohara T. et al. Mitogenic action of interleukin-1 alpha on vascular smooth muscle cells mediated by PDGF. Atherosclerosis 1990; 84 2-3 183-8.
10 Ikeda U, Ikeda M, Oohara T. et al. Interleukin 6 stimulates growth of vascular smooth muscle cells in a PDGF-dependent manner. Am J Physiol 1991; 260 (5 Pt 2) H1713-H1717.
11 Hajjar KA, Hajjar DP, Silverstein RL, Nachman RL. Tumor necrosis factor-mediated release of platelet-derived growth factor from cultured endothelial cells. J Exp Med 1987; 166 (01) 235-45.
12 Fukumoto Y, Shimokawa H, Ito A. et al. Inflammatory cytokines cause coronary arteriosclerosis-like changes and alterations in the smooth-muscle phenotypes in pigs. J Cardiovasc Pharmacol 1997; 29 (02) 222-31.
13 Feldman LJ, Aguirre L, Ziol M. et al. Interleukin-10 inhibits intimal hyperplasia after angioplasty or stent implantation in hypercholesterolemic rabbits. Circulation 2000; 101 (08) 908-16.
14 Schillinger M, Exner M, Mlekusch W. et al. Balloon angioplasty and stent implantation induce a vascular inflammatory reaction. J Endovasc Ther 2002; 9 (01) 59-66.
15 Schillinger M, Exner M, Mlekusch W. et al. Fibrinogen predicts restenosis after endovascular treatment of the iliac arteries. Thromb Haemost 2002; 87 (06) 959-65.
16 Schillinger M, Exner M, Mlekusch W. et al. Immediate and 6 months results after endovascular revascularistion below the knee: predictive value of C-reactive protein.. Radiology 2003 In press
17 Schillinger M, Exner M, Mlekusch W. et al. Restenosis after femoropopliteal PTA and Elective Stent Implantation: Potential Role of Monocyte Counts. J Endovasc Ther. In press.
18 Schillinger M, Exner M, Mlekusch W. et al. Acute phase response after carotid stenting: association with 6 months instent restenosis. Radiology. 2003 In press.
19 Danenberg HD, Welt FG, Walker M. et al. Systemic inflammation induced by lipopolysaccharide increases neointimal formation after balloon and stent injury in rabbits. Circulation 2002; 105 (24) 2917-22.
20 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 (07) 2168-73.
21 Wang X, Romanic AM, Yue TL. et al. Expression of interleukin-1beta, interleukin-1 receptor, and interleukin-1 receptor antagonist mRNA in rat carotid artery after balloon angioplasty. Biochem Biophys Res Commun 2000; 271 (01) 138-43.
22 Francis SE, Camp NJ, Dewberry RM. et al. Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease. Circulation 1999; 99 (07) 861-6.
23 Francis SE, Camp NJ, Burton AJ. et al. Interleukin 1 receptor antagonist gene polymorphism and restenosis after coronary angioplasty. Heart 2001; 86 (03) 336-40.
24 Momiyama Y, Hirano R, Taniguchi H, Nakamura H, Ohsuzu F. Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection. J Am Coll Cardiol 2001; 38 (03) 712-7.
25 Marculescu R, Endler G, Schillinger M. et al. Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes. Diabetes 2002; 51 (12) 3582-5.
26 Cox A, Camp NJ, Nicklin MJ. et al. An analysis of linkage disequilibrium in the interleukin-1 gene cluster, using a novel grouping method for multiallelic markers. Am J Hum Genet 1998; 62 (05) 1180-8.
27 Ranke C, Creutzig A, Alexander K. Duplex scanning of the peripheral arteries: correlation of the peak velocity ratio with angiographic diameter reduction. Ultrasound Med Biol 1992; 18 (05) 433-40.
28 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 (16) 3623-9.
29 Terwilliger J, Ott J.. Handbook of Human Genetic Linkage. Baltimore: Johns Hopkins University Press; 1994
30 Weir BS. Inferences about linkage disequilibrium. Biometrics 1979; 35 (01) 235-54.
31 Garnier-Gere P, Dillmann C. A computer program for testing pairwise linkage disequilibria in subdivided populations. J Hered 1992; 83 (03) 239.
32 Schneider S, Roessli D, Excoffier L. Arlequin. A software for population genetics data analysis. Ver 2.000. Genetics and Biometry Lab, Dept of Anthropology, University of Geneva. 2002
33 Zhao JH, Curtis D, Sham PC. Model-free analysis and permutation tests for allelic associations. Hum Hered 2000; 50 (02) 133-9.
34 El Omar EM, Carrington M, Chow WH. et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000; 404 6776 398-402.
35 Kastrati A, Dirschinger J, Schomig A. Genetic risk factors and restenosis after percutaneous coronary interventions. Herz 2000; 25 (01) 34-46.
36 Bauters C, Lamblin N, Amouyel P. Gene Polymorphisms and Outcome After Coronary Angioplasty. Curr Interv Cardiol Rep 2001; 3 (04) 281-6.
37 Roguin A, Hochberg I, Nikolsky E. et al. Haptoglobin phenotype as a predictor of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 2001; 87 (03) 330-2. A9
38 Jukema JW, Kastelein JJ. Tailored therapy to fit individual profiles. Genetics and coronary artery disease. Ann N Y Acad Sci 2000; 902: 17-24. discussion 24-6.: 17-24
39 Exner M, Schillinger M, Minar E. et al. Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with restenosis after percutaneous transluminal angioplasty. J Endovasc Ther 2001; 8 (05) 433-40.
40 Roubenoff R, Harris TB, Abad LW. et al. Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci 1998; 53 (01) M20-26.
41 Zee RY, Lunze K, Lindpaintner K, Ridker PM. A prospective evaluation of the interleukin-1 receptor antagonist intron 2 gene polymorphism and the risk of myocardial infarction. Thromb Haemost 2001; 86 (05) 1141-3.
42 Hurme M, Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol 1998; 28 (08) 2598-2602.
43 Wang X, Romanic AM, Yue TL. et al. Expression of interleukin-1beta, interleukin-1 receptor, and interleukin-1 receptor antagonist mRNA in rat carotid artery after balloon angioplasty. Biochem Biophys Res Commun 2000; 271 (01) 138-43.
44 Libby P, Schwartz D, Brogi E. et al. A cascade model for restenosis. A special case of atherosclerosis progression. Circulation 1992; 86 (Suppl. 06) (Suppl) III47-III52.
45 Jiang SL, Lozanski G, Samols D, Kushner I. Induction of human serum amyloid A in Hep 3B cells by IL-6 and IL-1 beta involves both transcriptional and post-transcriptional mechanisms. J Immunol 1995; 154 (02) 825-31.