Common Genetic Variants Linked To Cardiovascular Events
Researchers from Brigham and Women’s Thrombolysis in Myocardial Infarction (TIMI) Study group have found that approximately one third of the population has variations in a specific gene that renders them unable to metabolize properly clopidogrel, one of the most commonly prescribed anti-platelet medications.
Compared to people who did not have the variants in the cytochrome P-450 2C19 (CYP2C19) gene, those who possessed the variants had lower levels of the active metabolite of clopidogrel, less inhibition of platelets, and a significantly higher risk for major adverse cardiovascular events such as death, heart attack, stroke, and stent thrombosis (a serious blood clot formation following a stenting procedure). The findings appear today as an advance on-line publication for the New England Journal of Medicine.
“We found that patients with particular gene variants do not optimally respond to clopidogrel and therefore face a significantly higher risk of having a major cardiac event,” said Dr. Jessica Mega, lead author of the study and an Investigator at the TIMI Study Group as well as an Instructor of Medicine at Harvard Medical School. Dr. Mega explained that “the identification of this link could be an important part of targeting medicine to individual patients rather than treating everyone with one-size-fits-all therapies. In the future, doctors armed with this type of genetic information may be better positioned to care for patients suffering from heart attacks and other cardiovascular illnesses.”
The researchers found that in 162 healthy volunteers given clopidogrel, CYP2C19 genetic variant carriers had 32 percent lower levels of the active metabolite of clopidogrel and 25 percent less platelet inhibition as compared with those who did not have the variants. The CYP2C19 gene encodes an enzyme in the liver that is responsible for converting clopidogrel from an inactive prodrug into its active metabolite. Variation in the CYP2C19 gene is common in the general population, affecting 30 percent of Caucasians.
Building on those findings, the researchers examined outcomes in 1477 patients with acute coronary syndromes (heart attacks or unstable angina) who were treated with clopidogrel in the multinational TRITON-TIMI 38 study. They found that CYP2C19 genetic variant carriers had a 53 percent increase in risk for death, heart attacks, or strokes as compared with those who did not have the variants. They also found that those with the variants had a threefold increased risk of stent thrombosis, a life-threatening complication that can occur after coronary stenting.
Dr. Marc Sabatine, an Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School and senior author of the study, commented, “These data show that genes determine not only what diseases we have, but how we respond to medications. Patients who harbor one of these genetic variants are not getting the benefit from clopidogrel that their doctors think they will. Our results support the concept that genetics may be useful to tailor the pharmacotherapies we prescribe to our patients.”