AUTHOR=Li He , Zhang Yan-Jiao , Li Mu-Peng , Hu Xiao-Lei , Song Pei-Yuan , Peng Li-Ming , Ma Qi-Lin , Tang Jie , Zhang Wei , Chen Xiao-Ping 

TITLE=Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01039

DOI=10.3389/fphar.2018.01039

ISSN=1663-9812

ABSTRACT=<p>Dual antiplatelet treatment with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI). However, a portion of patients suffer from clopidogrel resistance (CR) and consequently with recurrence of cardiovascular events. Genetic factors such as loss-of-function variants of <italic>CYP2C19</italic> contribute a lot to CR. Recently, the N-6-adenine-specific DNA methyltransferase 1 (<italic>N6AMT1</italic>) rs2254638 polymorphism is reported to be associated with clopidogrel response. To validate the association between <italic>N6AMT1</italic> rs2254638 polymorphism and clopidogrel response, 435 Chinese CAD patients receiving aspirin and clopidogrel were recruited. <italic>N6AMT1</italic> rs2254638 and <italic>CYP2C19</italic><sup>*</sup><italic>2/</italic><sup>*</sup><italic>3</italic> polymorphisms were genotyped. Platelet reaction index (PRI) was measured by VASP-phosphorylation assay after treated with a 300 mg loading dose (LD) clopidogrel or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days. There was a significant difference in PRI between LD cohort and MD cohort. Carriers of <italic>CYP2C19</italic><sup>*</sup><italic>2</italic> allele showed significantly increased PRI in the entire cohort and in respective of the MD and LD cohorts <italic>(p</italic> &lt; 0.001, <italic>p</italic> = 0.003, <italic>p</italic> &lt; 0.001, respectively). However, carriers of <italic>CYP2C19</italic><sup>*</sup><italic>3</italic> allele exhibited significantly higher PRI only in the entire cohort and LD cohort (<italic>p</italic> = 0.023, <italic>p</italic> = 0.023 respectively). PRI value was significantly higher in <italic>CYP2C19</italic> PM genotyped patients as compared with those carrying the IM genotypes and EM genotype (<italic>p</italic> &lt; 0.001). Besides, carriers of the rs2254638 C allele showed significantly higher PRI in entire cohort and in the LD cohort <italic>(p</italic> = 0.023<italic>, p</italic> = 0.008, respectively). When the patients were grouped into clopidogrel resistance (CR) and non-clopidogrel resistance (non-CR) groups, <italic>CYP2C19</italic><sup>*</sup><italic>2</italic> was associated with increased risk of CR in the entire cohort, the LD cohort and the MD cohort <italic>(p</italic> &lt; 0.001<italic>, p</italic> &lt; 0.001, and <italic>p</italic> = 0.019, respectively). Carriers of the rs2254638 C allele also showed increased risk of CR in the entire cohort and the LD cohort <italic>(p</italic> = 0.024, and <italic>p</italic> = 0.028, respectively<italic>)</italic>. N6AMT1 rs2254638 remained as a strong predictor for CR (TC vs. TT: OR = 1.880, 95% CI = 1.099–3.216,<italic>p</italic> = 0.021<italic>;</italic> CC vs. TT: OR = 1.930, 95% CI = 1.056-3.527, <italic>p</italic> = 0.032; TC + CC vs. TT: OR = 1.846, 95%CI = 1.126–3.026, <italic>p</italic> = 0.015) after adjustment for confounding factors. Our study confirmed the influence of <italic>CYP2C19</italic><sup>*</sup>2 and rs2254638 polymorphisms on clopidogrel resistance in Chinese CAD patients. Both <italic>CYP2C19</italic><sup>*</sup><italic>2</italic> and <italic>N6AMT1</italic> rs2254638 polymorphism may serve as independent biomarkers to predict CR.</p>