A genome-wide association study identifies novel genetic loci modifying pharmacokinetic - pharmacodynamic responses to clopidogrel

摘要

Aim Clopidogrel therapy is associated with a substantial variability in pharmacokinetics （PK） and pharmacodynamics （PD） responses. To date, known gene variants explain only a small proportion of the variabili- ty. A genome-wide association study （GWAS） was conducted to identify new genetic loci modifying PD responses to clopidogrel in Chinese patients with coronary heart disease （CHD）. The initial GWAS by combination analysis of PIL/PD included 115 patients with CHD. The PK validation included 31 patients with CHD and the metabolizing functional validation included 32 human liver tissues. We identified novel variants in two transporter genes （ rs12456693 in SLC14A2 and kgpl 1138762 in ABCA1 ） and in N6AMT1 （rs2254638） associated with not only clo- pidogrel on-treated P2Y12 reaction unit （PRU） （P 〈 1 × 10^-4） , but also plasma clopidogrel active metabolite H4 concentration （P 〈 1 × 10^-2）. The significant association between rs12456693, kgpl 1138762, or rs2254638 and PK parameters of clopidogrel （P 〈 1 × 10^-2） was observed in additional CHD patients. Further, the N6AMT1 rs2254638 T variant was found to be associated decreased activation of clopidogrel （P -3.86 × 10^-2）. The new variants in N6AMT1 and ABCA1, together with CYP2C19 ＊ 2, dramatically improve the predictability of PRU varia- bility to 37.7% compared with the published value of approximately 20%. The present study identifies novel genet- ic loci modifying PIL/PD responses to clopidogrel, which contributes to a better understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.