Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy
Shuldiner AR, O'Connell JR, Bliden KP, et al
JAMA. 2009;302:849-857
Summary
The authors of this study had 3 aims: (1) to establish whether laboratory response to clopidogrel is an inherited trait; (2) to identify genetic variants that predict platelet inhibitory response to clopidogrel; and (3) to demonstrate the clinical importance of these variants by association with clinical outcomes.
First, by studying a large population of related Amish individuals, they demonstrated that laboratory response to clopidogrel is a highly heritable trait. Furthermore, the authors estimated that the genetic contribution far outweighs non genetic contributions such as age, body mass index, and lipids.
To meet their second objective, the authors used the same population to conduct a genome wide screen of more than 500,000 genetic variants and found that 1 variant, CYP2C19*2, was most closely associated with poor laboratory response to 7 days of clopidogrel dosed at 75 mg/day. Individuals carrying 2 copies of this genetic variant receive, on average, a 40% inhibition in platelet aggregation with clopidogrel. In contrast, those who do not carry this genetic variant have 65% inhibition with clopidogrel.
Finally, by genotyping a large group of patients undergoing elective percutaneous coronary intervention, the authors demonstrated that patients who carry the CYP2C19*2 variant experience a reduced platelet inhibitory response to clopidogrel and have a 3- to 4-fold increased risk for cardiovascular events in the subsequent year. Most important, the authors also demonstrated that patients were not at an increased risk for events when not treated with clopidogrel.
Viewpoint
Clopidogrel, along with aspirin, forms the cornerstone of antiplatelet therapy for the prevention of death and myocardial infarction after acute coronary syndromes and percutaneous coronary interventions. Recently, investigators have identified a genetic variant named CYP2C19*2 that leads to a loss of function in the CYP2C9 enzyme, which is required to activate clopidogrel once absorbed. Determination of whether additional genetic variants are also important was the basis of the current study.
Before embarking on an in-depth genetic study, it is critical to establish that the outcome of interest -- in this case, the platelet inhibitory response to clopidogrel -- is in fact under genetic control. To do this requires a large group of related individuals in whom the outcome is systematically measured in all. The authors of this study turned to a group of healthy Old Order Amish who are known to be related and administered clopidogrel to them all. By using known relationships between individuals and their laboratory response to clopidogrel, these authors are the first to demonstrate that genetics play a large role in the response to clopidogrel. This observation lays the foundation for their further genetic investigations.
The genetic variant identified in this study had been identified by others and, thus, this study represents an independent validation of the negative effects that the CYP2C19*2 variant confers on patients treated with clopidogrel. Yet, because the authors also measured the pre-clopidogrel platelet aggregation in their populations, they were also able to show that this genetic variant was not associated with differences in platelet aggregation before the administration of clopidogrel. This observation is important, since it helps to establish that this variant, by itself, is not associated with increased platelet aggregation and instead is only important in the presence of clopidogrel. Furthermore, they demonstrate that this variant is associated with an increased risk for future events only in the presence of clopidogrel therapy. Thus, carriers of this variant who are not treated with clopidogrel are not at an increased risk for cardiovascular events. This last point is important because some have suggested that the association with increased events in carriers of this variant is due to confounding or independent, deleterious effects of the variant. Instead, the current results suggest that the adverse effects of this variant are entirely mediated through its impairment of clopidogrel's antiplatelet effect.
Finally, this study is notable for the absence of any additional genetic variants outside of CYP2C19*2. Despite demonstrating that the response to clopidogrel is largely under genetic control, it is surprising that no additional variants were identified. This discrepancy suggests that further research is needed to identify additional genes not investigated in this study, including rare genetic variants or other forms of genetic variation such as gene duplications or deletions that may confer genetically mediated clopidogrel resistance.
Abstract