Genetic determinants of high on-treatment platelet reactivity in clopidogrel treated Chinese patients

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• 作者：Lanning Zhang ; Yanming Chen ; Ying Jin ; Fei Qu ; Jiayue Li ; Cong Ma ; Jie Yang ; Bin Xu ; Hongjuan Wang ; Xiaoqi Li ; Yang Li ; Yuxiao Zhang ; Caiyi Lu ; Tong Yin
• 关键词：Clopidogrel ; Pharmacogenetics ; Platelet reactivity ; CYP2C19 ; ABCB1 ; PON1
• 刊名：Thrombosis Research
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：132
• 期：1
• 页码：81-87
• 全文大小：417 K

文摘

Introduction

Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genetic polymorphisms in these genes have been associated with the variability of the response to clopidogrel, however their contribution to high on-treatment platelet reactivity (HPR) in clopidogrel treated Chinese patients is less known.

Materials and methods

Five-hundred Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese People¡¯s Liberation Army, from September 2010 to September 2012. We assessed the relations of CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5 days maintenance dose of clopidogrel administration, and the risk for HPR. The cutoff of HPR was defined as 20 ¦Ìmol/L adenosine diphosphate (ADP)-induced platelet aggregation > 50 % .

Results

Both CYP2C19*2 and *3 alleles were significantly associated with higher platelet aggregation after 5 days maintenance dose of clopidogrel administration (P < 0.00001and P = 0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss-of-function allele (*2 or *3, accounted for 58 % of the study population) was obviously higher than that in non-carriers (P < 0.00001). Patients with the CYP2C19*2 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype [adjusted hazard ratio (HR), 1.56; 95 % confidence interval(CI), 1.04-2.33, P = 0.03]. The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR1.79,95 % CI: 1.33-2.4,P = 0.003). However, the carriage of CYP2C19*3 alone could not predict the risk of HPR significantly (adjusted HR, 1.5; 95 % CI: 0.83-3, P = 0.16). Significant relation of CYP2C19*17, PON1Q129R and ABCB1C3435T to the platelet aggregation was not found.

Conclusion

In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. Neither ABCB1 nor PON1 genotype could influence the antiplatelet response of clopidogrel in the cohort of Chinese patients.