Researchers at the University of Maryland School of Medicine report that a common gene variant plays a role in decreasing patients’ response to Plavix (clopidrogel), an anticlotting medication from sanofi-aventis and Bristol-Myers Squibb. They say that this CYP2C19 variant constitutes about 12% of the platelet response to the drug.
“We didn't detect any other common gene variants that appear to be as significant as CYP2C19, but our research suggests that people's response to clopidrogel is largely inherited and additional common and rare gene variants most likely are involved,” says Alan R. Shuldiner, M.D., professor of medicine and director of the program in genetics and genomic medicine. He is also the lead author of the paper published in the August 26 issue of the Journal of the American Medical Association (JAMA).
The team analyzed the DNA of 429 healthy members of the Amish community in Lancaster County, PA. Dr. Shuldiner explains that about 30% of the Amish population has the CYP2C19 variant, which is similar to the general population. The study participants were given Plavix for seven days. The researchers then looked at how their blood platelets responded and used genome-wide association studies to look for associated gene variations.
The researchers collaborated with investigators at the Sinai Center for Thrombosis Research, confirming their findings by studying a group of 227 people who received Plavix after having stents implanted to open blocked coronary arteries at Sinai Hospital.
“Patients with the CYP2C19 variant had a diminished platelet response to clopidrogrel treatment and poorer cardiovascular outcomes,” according to Paul A. Gurbel, M.D., senior author of the study and director of the Sinai Center for Thrombosis Research. “Patients with the gene variant were more likely (20.9% vs. 10%) to have a heart attack or other serious cardiovascular event in the year following initiation of treatment.”
Dr. Shuldiner goes on to explain that by studying the Amish, a genetically homogenous people, they estimated that 70% of the variation in clopidrogel response is due to genes and other shared factors among family members, such as their environment. In genetic research, 70% is considered extremely high heritability, he says.
The researchers say that the CYP2C19 variant accounts for about 12% of the platelet response to the drug, and other factors such as age, body mass index, and cholesterol levels in the blood account for another 10%. Dr. Shuldiner notes, however, that most of the difference in response to the medicine remains unexplained. “Additional studies in larger populations will be necessary to find additional genes that influence response to clopidogrel.”
About 30% of the general population in the U.S. reportedly has the CYP2C19 variant that was identified in the study. Dr. Shuldiner says that it could be detected by a test using DNA from blood or saliva. “If people have the gene variant, they might need to take a higher dose of clopidrogel or a different medication altogether,” he notes, adding that more research is needed before such testing becomes routine.