title: Inflammation and apoptosis genes and the risk of restenosis after percutaneous coronary intervention.
abstract: OBJECTIVE
  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-1beta 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-1beta 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.
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pascalle S
authors.initials: PS
authors.lastname: Monraats
authors.forename: Florentine
authors.initials: F
authors.lastname: de Vries
authors.forename: Laura W
authors.initials: LW
authors.lastname: de Jong
authors.forename: Douwe
authors.initials: D
authors.lastname: Pons
authors.forename: Varsha D K D
authors.initials: VD
authors.lastname: Sewgobind
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: Moniek P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: de Winter
authors.forename: René A
authors.initials: RA
authors.lastname: Tio
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Arnoud
authors.initials: A
authors.lastname: van der Laarse
authors.forename: Ernst E
authors.initials: EE
authors.lastname: van der Wall
authors.forename: J
authors.initials: J
authors.lastname: Wouter Jukema
mesh_terms: D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D020170:Caspase 1 / Q000235:genetics; D023903:Coronary Restenosis / Q000150:complications / Q000235:genetics*; D017931:DNA Primers; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007375:Interleukin-1 / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D017931:DNA Primers; D007375:Interleukin-1; D020170:Caspase 1