Variants of three genes related to clopidogrel metabolism and platelet receptor function – CYP2C19, ABCB1, and ITGB3 – appear to be independent risk factors for early stent thrombosis, beyond the already known clinical and angiographic risk factors, according to a report in the Oct. 26 issue of JAMA.
A risk-prediction model that incorporated both genetic and clinical data had greater sensitivity and specificity at predicting early stent thrombosis than did a clinical model alone, said Dr. Guillaume Cayla of Institut de Cardiologie, INSERM Unite Mixte de Recherche, Salpetriere Hospital, Paris, and his associates.
The researchers assessed all of the 23 genetic variants that have been reported to correlate with clopidogrel pharmacogenetics and arterial thrombosis to determine which ones contribute most to early stent thrombosis.
They used a nationwide French registry of patients who had definite stent thrombosis within 30 days of implantation to identify 123 cases, then matched these for age and sex with 246 control subjects who had no stent thrombosis. Peripheral blood samples from these 369 subjects were genotyped for the suspect genetic variations.
Only four variations in three genes were found to be significantly associated with early stent thrombosis.
First, the CYP2C19 loss-of-function allele occurred in 49% of cases but only 26% of controls. Second, the CYP2C19 gain-of-function allele occurred in only 20% of cases but in 33% of controls. These findings strengthen the current evidence that CYP2C19 plays a predominant role in clopidogrel metabolism, Dr. Cayla and his colleagues said.
"The effects of different genes according to different ethnic groups may warrant dedicated studies."
Third, an ABCB1 variant occurred in 32% of cases but only 19% of controls. "The ABCB1 gene encodes a drug efflux transporter, P-glycoprotein, that modulates clopidogrel absorption. It has been previously associated with reduced clopidogrel response, but with variable clinical consequences," they noted.
And fourth, an ITGB3 variant occurred in only 16% of cases but 28% of controls. The ITGB3 gene encodes for integrin beta-3, "a component of the glycoprotein IIb/IIIa platelet receptor, which mediates the final pathway of platelet aggregation," they said.
There was a dose-response relationship in that risk of early stent thrombosis climbed steadily with carriage of an increasing number of these risk alleles, the investigators said.
A risk-prediction model that combined genetic data with clinical data had significantly greater power to predict early stent thrombosis than did a clinical model alone. The combined model had 67% sensitivity and 79% specificity in this regard, compared with 60% sensitivity and 70% specificity for the model using only clinical data.
"Patients in the highest tertile of risk using the combined clinical and genetic model had a sevenfold increased risk of early stent thrombosis vs. patients in the lowest tertile," Dr. Cayla and his associates said (JAMA 2011;306:1765-74).
The researchers also found that two nongenetic factors – loading dose of clopidogrel and the concomitant use of proton pump inhibitors (PPIs) – were significantly related to early stent thrombosis. Cases were much more likely than controls to have received a low loading dose of clopidogrel at stent implantation. And cases also were much more likely than controls to be taking PPIs, which have been suspected of interfering with clopidogrel metabolism.
Unlike the genetic risk factors, both clopidogrel dose and PPI use are modifiable risk factors, they noted.
This study was limited in that patients with the most severe early stent thrombosis died before they could be included in the study, so the genotype-phenotype relation remains unknown for them. "Stent malappositions or underexpansions are other important factors associated with stent thrombosis that were not evaluated," the investigators said.
In addition, the study findings may apply only to white patients because virtually all the subjects, who were drawn from the general population in France, were white. "The effects of different genes according to different ethnic groups may warrant dedicated studies," they added.
This study was funded by ACTION, the Société Francaise de Cardiologie, the Fédération Francaise de Cardiologie, and INSERM. The French registry of patients with early stent thrombosis was partially supported by Eli Lilly and the SGAM Foundation. Dr. Cayla and his associates reported ties to numerous industry sources.