Huang Tao-Sheng, Zhang Ling, He Qiong, Li Yu-Bin, Dai Zhong-Li, Zheng Jian-Rui, Cheng Pei-Qi, He Yun-Shao
Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Rd. 2, Guangzhou, Guangdong, 510080, People's Republic of China.
Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
Australas Phys Eng Sci Med. 2017 Mar;40(1):249-258. doi: 10.1007/s13246-016-0519-x. Epub 2017 Jan 12.
The optimal dose of warfarin depends on polymorphisms in the VKORC1 (the vitamin K epoxide reductase complex subunit (1) and CYP2C9 (cytochrome P450 2C9) genes. To minimize the risk of adverse reactions, warfarin dosages should be adjusted according to results from rapid and simple monitoring methods. However, there are few pharmacogenetic-guided warfarin dosing algorithms that are based on large cohorts from the Chinese population, especially patients with atrial fibrillation. This study aimed to validate a pharmacogenetic-guided warfarin dosing algorithm based on results from a new rapid electrochemical detection method used in a multicenter study. Three SNPs (CYP2C9 *2, *3 and VKORC1 c.-1639G > A) were genotyped by electrochemical detection using a sandwich-type format that included a 3' short thiol capture probe and a 5' ferrocene-labeled signal probe. A total of 1285 samples from four clinical hospitals were evaluated. Concordance rates between the results from the electrochemical DNA biosensor and the sequencing test were 99.8%. The results for gene distribution showed that most Chinese patients had higher warfarin susceptibility because mutant-type and heterozygotes were present in the majority of subjects (99.4%) at locus c.-1639G > A. When the International Warfarin Pharmacogenetics Consortium algorithm was used to estimate therapeutic dosages for 362 patients with AF and the values were compared with their actual dosages, the results revealed that 56.9% were similar to actual dosages (within the 20% range). A novel electrochemical detection method of CYP2C9 *2, *3and VKORC1 c.-1639G > A alleles was evaluated. The warfarin dosing algorithm based on data gathered from a large patient cohort can facilitate the reasonable and effective use of warfarin in Chinese patients with AF.
华法林的最佳剂量取决于维生素K环氧化物还原酶复合体亚基1（VKORC1）和细胞色素P450 2C9（CYP2C9）基因的多态性。为将不良反应风险降至最低，应根据快速简便的监测方法结果调整华法林剂量。然而，基于中国人群尤其是房颤患者的大样本队列研究的药物遗传学指导的华法林给药算法却很少。本研究旨在基于一项多中心研究中使用的新型快速电化学检测方法的结果，验证一种药物遗传学指导的华法林给药算法。采用夹心型检测形式，通过电化学检测对三个单核苷酸多态性（CYP2C9 *2、*3和VKORC1 c.-1639G＞A）进行基因分型，该检测形式包括一个3'短硫醇捕获探针和一个5'二茂铁标记信号探针。对来自四家临床医院的1285份样本进行了评估。电化学DNA生物传感器与测序检测结果的一致性率为99.8%。基因分布结果显示，大多数中国患者对华法林的敏感性较高，因为在c.-1639G＞A位点，大多数受试者（99.4%）存在突变型和杂合子。当使用国际华法林药物遗传学联盟算法估算362例房颤患者的治疗剂量并将这些值与其实际剂量进行比较时，结果显示56.9%与实际剂量相似（在20%范围内）。评估了一种新型的CYP2C9 *2、*3和VKORC1 c.-1639G＞A等位基因的电化学检测方法。基于大量患者队列收集的数据得出的华法林给药算法，有助于中国房颤患者合理有效地使用华法林。
