Inflammation and apoptosis genes and the risk of restenosis after percutaneous coronary intervention.
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.
Monraats
Pascalle S
PS
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
de Vries
Florentine
F
de Jong
Laura W
LW
Pons
Douwe
D
Sewgobind
Varsha D K D
VD
Zwinderman
Aeilko H
AH
de Maat
Moniek P M
MP
't Hart
Leen M
LM
Doevendans
Pieter A
PA
de Winter
Robbert J
RJ
Tio
René A
RA
Waltenberger
Johannes
J
Frants
Rune R
RR
van der Laarse
Arnoud
A
van der Wall
Ernst E
EE
Wouter Jukema
J
J
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
D017931:DNA Primers; D007375:Interleukin-1; D020170:Caspase 1