Cyp2c19 gene copy number variations and clopidogrel pharmacogenetics: association of gene dosage and cardiovascular events in sardinian and italian continental patients with acute coronary artery syndromes

Variability in pharmacokinetics and drug response accounts for single-nucleotide variants/ polymorphisms (SNVs/SNPs) as well as copy-number variants (CNVs). While the role of SNVs/SNPs on drugs metabolism has been extensively studied, little is known about the CNVs. Cytochrome P450 2C19 (CYP2C19) gene variants and their overall effects on the clinical outcomes of patients with Acute Coronary Syndromes (ACS) treated with Clopidogrel in a dual antiplatelets therapy, remain still controversial although bed-side genetic-driven care has been shown to be feasible. We sought to evaluate the impact of CYP2C19 CNVs on the clinical outcomes in Sardinian patients who underwent percutaneous coronary interventions (PCI) and received clopidogrel therapy having as control population Italian continental (Sicilian ancestry included). The prevalence of CYP2C19 CNVs were assessed by means of three dedicated TaqMan assays (Hs05148033_cn, Hs02932336_cn and Hs05107177_cn) in 100 Sardinian patients who underwent PCI. The control population was made of 200 Italian continental patients (of whom 60 individuals of Sicilian ancestry). Clinical relevant outcomes (adverse cardiovascular events, stent thrombosis and bleeding) and CYP2C19 CNVs were then associated in these two groups. The primary observation was the identification of CYP2C19 gene CNVs in the Sardinian population at higher rate: 7.2% of deletion and 3.2% of duplication alleles respectively in Sardinian vs 1.2% and 0.7% in the control group. The second finding showed that the CYP2C19 deletion allele is at increased risk of a composite of cardiovascular death, myocardial infarction, symptom-driven revascularisation compared with non-carriers (10.58% vs 6.07%, OR: 1.99, 95% CI, pz<0.001). Stent thrombosis (ST) is also more frequent in the deletion allele carriers (2.22% vs 0.44%, OR: 4.77, 95% CI, p<0.001). The risk of bleeding is higher in the duplication allele carriers. In conclusion, genetic testing including the search for CNVs, may be helpful to personalize patients’ care being the dual antiplatelets therapy pivotal for patients undergoing PCI.