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Inflammation and apoptosis genes and the risk of restenosis after percutaneous coronary intervention

Monraats, Pascalle S.a d; de Vries, Florentinea; de Jong, Laura W.a; Pons, Douwea; Sewgobind, Varsha D.K.D.a; Zwinderman, Aeilko H.e; de Maat, Moniek P.M.g; ‘t Hart, Leen M.b; Doevendans, Pieter A.h; de Winter, Robbert J.f; Tio, René A.i; Waltenberger, Johannesj; Frants, Rune R.c; van der Laarse, Arnouda; van der Wall, Ernst E.a; Wouter Jukema, J.a d

doi: 10.1097/01.fpc.0000220572.28585.5e
ORIGINAL ARTICLES
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Objectives Genetic factors appear to be important in the development of restenosis after percutaneous coronary intervention, as well as in the process of inflammation, a pivotal factor in restenosis. Caspase-1, interleukin-1-receptor and protein tyrosine phosphatase nonreceptor type 22 are important mediators in the inflammatory response and caspase-1 also in apoptosis. Therefore, we examined whether polymorphisms in these candidate genes are related to the risk of developing restenosis after percutaneous coronary intervention.

Methods The GENetic DEterminants of Restenosis-project is a multicenter prospective follow-up study. The 5352G/A (L235L) caspase-1-polymorphism, the 7464C/G (A124G) interleukin-1r-polymorphism and the 1858C/T (R620W) protein tyrosine phosphatase nonreceptor type 22-polymorphism were genotyped. To examine the functional effect of the caspase-1 polymorphism, mature plasma interleukin-1β levels were measured by enzyme-linked immunosorbent assay in lipopolysaccharide-stimulated whole blood from a subpopulation of patients.

Results A total of 3104 patients, age 62.1±10.7 years, were included after successful percutaneous coronary intervention. A significant association between the 5352AA genotype of the caspase-1 gene and target vessel revascularization (relative risk 2.2, 95% confidence interval 1.32–3.76) was observed after correcting for clinical variables. Angiographic analysis of a subgroup of patients (N=478) also showed an increased risk for developing restenosis for patients having the 5352GA/AA genotype (P=0.001). The results were corroborated, although they were not statistically significant, by somewhat higher mature interleukin-1β levels in patients with the 5352AA genotype.

Conclusions The present study shows that patients with the 5352AA genotype in the caspase-1 gene are at increased risk of developing restenosis. If confirmed by other studies, screening patients for this genotype can lead to better risk stratification and provide indications for improving individual treatment; for instance, by providing a new target for drug-eluting stents.

Departments of aCardiology

bMolecular Cell biology, Leiden University Medical Center

cDepartment of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden

dInteruniversity Cardiology Institute of the Netherlands (ICIN), Utrecht

Departments of eMedical Statistics

fCardiology, Academic Medical Center, Amsterdam

gDepartment of Hematology, Erasmus University Medical Center, Rotterdam

hDepartment of Cardiology, University Medical Center Utrecht, Utrecht

iDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen

jDepartment of Cardiology, Academic Hospital Maastricht, Maastricht, The Netherlands

Correspondence and requests for reprints to J. Wouter Jukema, MD, PhD, FESC, FACC, Professor of Cardiology, Chairman ‘Leiden Vascular Medicine’, Department of Cardiology C5-P Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.

Tel: +31 71 5266695; fax: +31 71 5266885; e-mail: j.w.jukema@lumc.nl

Sponsorship: P.S. Monraats is supported by grant 99.210 from the Netherlands Heart Foundation and a grant from the Interuniversity Cardiology Institute of the Netherlands (ICIN). Dr J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (2001 D 032). The study was supported by the Centre for Medical Systems Biology (CMSB), a center of excellence approved by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NWO).

Received 24 January 2006 Accepted 24 April 2006

© 2006 Lippincott Williams & Wilkins, Inc.