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PGx Highlights from American College of Cardiology Annual Meeting


This article was originally posted March 29.

The annual meeting of the American College of Cardiology held last week in Chicago featured a number of pharmacogenomically guided studies related to treatments for cardiovascular disease.

The following is a roundup of some of the meeting's pharmacogenomics highlights.

Lack of Association in SLCO1B1 Polymorphisms and Clinical Myalgia after Crestor Treatment

Researchers led by Jacqueline Suk Danik from Brigham and Women's Hospital investigated whether individuals who are carriers of SCLCOB1 rs4363657C and rs4149056C have increased incidence of myopathic complaints when taking AstraZeneca's Crestor (rosuvastatin) compared to non-carriers. In past studies, researchers have seen a similar influence in patients taking Merck's Zocor (simvastatin).

Danik et al. retrospectively genotyped patients receiving Crestor in the JUPITER trial. The original study randomized 4,400 people without heart disease or diabetes to Crestor or placebo. "Among those allocated to active rosuvastatin, there was no difference in [the] rate of myalgia among carriers of the rs4363657C allele or the rs4149056C allele when compared to non-carriers," the researchers found. The researchers had similar findings even after expanding their definition of myalgia to include complaints of muscle weakness, stiffness, or pain.

"In contrast to data for simvastatin, there appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C allele or the rs4149056C allele in the SLCO1B1 gene," Danik et al. concluded.

AstraZeneca, the National Cancer Institute, and the National Heart, Lung, and Blood Institute provided funding for this study.

Impact of CYP2C19 and CYP3A5 Genotypes in Patients Undergoing Stent Procedures, Treated with Maintenance Dose Plavix

Studies have shown that patients with high platelet reactivity after being treated with Bristol-Myers Squibb's Plavix (clopidogrel) may be at increased risk of stent thrombosis after undergoing a stent procedure. Researchers led by Tadasuke Chitose of Kumamoto University examined CYP2C19 and CYP3A5 genotypes, as well as platelet aggregation, in 62 patients. Platelet reactivity was measured twice, after patients received a loading dose (300 mg/day) of Plavix, and then after they received a maintenance dose (75 mg/day) of the drug.

In the study, 31 percent, 42 percent, and 27 percent of patients were extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. After patients received 300 mg/day of Plavix, platelet reactivity was 4,069 +/-1,383; 4,407 +/-1,755; and 5,301 +/-807 AU*min in the extensive, intermediate, and poor metabolizer groups, respectively. After receiving the maintenance dose of Plavix, platelet reactivity levels were 2,948 +/-1,427; 3,068 +/-1,656; and 4,465 +/-1,557 AU*min in the extensive, intermediate, and poor metabolizer groups, respectively.

With regards to CYP3A5 genotypes, 32 percent were wild-type or carried one loss-of-function allele and 68 percent of participants carried two loss-of-function alleles. Platelet reactivity in CYP2C19 poor metabolizers after receiving 75 mg/day maintenance dose of Plavix was 3,398 +/-1,143 and 5,175 +/-1,415 AU*min in CYP3A5 expressor and non-expressor groups, respectively.

Based on the data, Chitose et al concluded that antiplatelet response after receiving a maintenance dose of Plavix might depend on CYP3A5 polymorphism in patients with CYP2C19 poor metabolizer status.

Gene Expression Profiling in Circulating Microparticles in Acute Coronary Syndrome Patients

Researchers led by Luigi Biasucci of Catholic University in Rome characterized mRNA expression in microparticles in 16 acute coronary syndrome patients with non-ST elevated myocardial infarction and 16 patients with stable angina. The researchers then compared the gene-expression profile of these patients to a control group of 17 healthy adults.

A PCR array was used to gauge mRNA expression in atherosclerosis and transcription pathways, according to the abstract. After analyzing 168 genes and comparing mRNA expression between study groups, the researchers identified five modulated genes for the atherosclerosis pathway that distinguished between myocardial infarction and stable angina patients.

"Elastin, matrix metalloproteinase-1, and selectin showed differences in mRNA with a fold change greater than five in [myocardial infarction] versus stable angina [patients]," reported Biasucci et al. in the abstract. "On the contrary, angiotensin I converting enzyme and neuropeptide Y mRNA were down-regulated in [myocardial infarction patients]."

Additionally, in the transcription pathway, researchers identified eight modulated genes. Androgen receptor, forkhead box 01, MYC associated factor , nuclear factor of kappa light polypeptide gene, V-rel reticuloendotheliosis viral oncogene, and signal transducer and activator of transcription 4, were down-regulated in myocardial infarction patients but not in stable angina patients. Meanwhile, general transcription factor IIB was up-regulated in myocardial infarction patients as opposed to stable angina patients.

"Our study revealed a different microparticle mRNA profile in [myocardial infarction] patients compared to stable angina patients," Biasucci et al. concluded. "The higher difference mRNA expression were found among proteins involved in extracellular matrix synthesis or degradation, leukocyte infiltration and inflammation, suggesting a role of microparticles also on plaque instability (possibly also as a counter-regulatory mechanism) and myocardial damage and as a potential novel therapeutic target."

Pilot Study of Outpatient 2C19 Screening to Adjust Plavix Dose

Researchers led by Joseph Rossi of the University of North Carolina, Chapel Hill, sought to assess a genotype-driven treatment strategy for stable percutaneous coronary intervention patients in the outpatient setting by screening them for CYP2C19*2 loss-of-function alleles, noting that such a strategy is not recommended in clinical practice.

Rossi et al. genotyped more than 200 patients with a history of PCI receiving chronic aspirin and Plavix (clopidogrel) for CYP2C19 alleles and platelet function. If patients had at least one CYP2C19*2 allele they were crossed over to a study comparing 75 mg/day of Plavix compared to 150 mg/day of Plavix for 30 days. The researchers also measured platelet aggregation and blood metabolite in these patients.

While patients were receiving standard doses of the drug, CYP2C19*2 carriers had elevated platelet reactivity compared to wild-type patients. Meanwhile, carriers of the gain-of-function allele, CYP2C19*17, had similar platelet reactivity as wild-type patients.

In the crossover study, researchers enrolled 50 patients with at least one CYP2C19*2 allele. In these patients, 150 mg/day of Plavix was linked to improved ADP-specific platelet inhibition compared to 75 mg/day of the drug. Platelet reactivity was "poorly correlated" with blood metabolite levels, the researchers found.

"Carriers of CYP2C19*2 displayed increased platelet reactivity compared to non-carriers," the researchers concluded. "CYP2C19*17 carrier status did not affect platelet function."

The data from this investigation led Rossi et al. to conclude that "treatment with 150 mg/day of clopidogrel reduced, but did not eliminate, the increased platelet reactivity seen in CYP2C19*2 carriers." Furthermore, platelet reactivity levels "correlated poorly with measured active metabolite levels."