Editors' ChoiceCardiovascular Disease

Genetic Markers of In-Stent Thrombosis

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Science Translational Medicine  09 Nov 2011:
Vol. 3, Issue 108, pp. 108ec182
DOI: 10.1126/scitranslmed.3003404

More than 1 million patients with heart attacks have benefited from percutaneous coronary intervention, in which blocked arteries are cleared and tube-like stents are inserted to keep them open. Despite the use of anticlotting and antiplatelet therapies such as aspirin and clopidogrel, deadly thromboses can form in the stent within a month after insertion. These tend to occur when antiplatelet therapy is prematurely discontinued, in patients who also have diabetes, or when the atherosclerotic lesions are complex. As a first step toward unearthing genetic markers that could improve prediction of this serious complication, Cayla et al. performed a case-controlled analysis in 123 patients with such early in-stent thrombosis of 23 genetic variants in 15 different genes.

Some of these genes were related to the responsiveness to, absorption of, and metabolism of clopidogrel, whereas others encode key factors of the coagulation and fibrinolytic systems and platelet receptor functions. By comparing single-nucleotide polymorphisms in these 123 patients and to those in 246 matched patients without early in-stent thrombosis, the authors identified CYP2C19 metabolic status, ABCB1 3435 TT genotype, and ITIGB3 PLA2 status as significant determinants of early in-stent thrombosis. A similar analysis also identified common, known nongenetic predictors such as diabetes, decreased ejection fraction, proton pump inhibitor use, and high clopidogrel loading dose, confirming the validity of the approach. Although the predictive accuracy of the genetic-only model (positive likelihood ratio of 2.0) was comparable with that of the clinical-only model (positive likelihood ratio of 2.1), the combination of the two models generated a statistically significant increase in predictive power (positive likelihood ratio of 3.4).

The CYP2C19 gene encodes a variant of hepatic cytochrome P450 2C19 and contributes to variability in clopidogrel responsiveness; ABCB1 3435 TT encodes a drug efflux transporter that modulates clopidogrel absorption; and the ITGB3 gene encodes a component of platelet receptor function and aggregation. That these genes are involved in clopidogrel metabolism and general coagulation networks made sense for their predictive role in early in-stent thrombosis and suggest that they could also be attractive drug targets. Soon, we may be able to better care for patients by using a risk-adapted strategy based on a combination model of clinical, radiographic, laboratory, and genetic risk factors.

G. Cayla et al., Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA 306, 17651774 (2011). [Abstract]

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