Krishna Kumar Dhakchinamoorthi, Shewade Deepak Gopal, Loriot Marie-Anne, Beaune Philippe, Balachander Jayaraman, Sai Chandran B V, Adithan Chandrasekaran
Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, 605 006, India,
Eur J Clin Pharmacol. 2014 Jan;70(1):47-56. doi: 10.1007/s00228-013-1581-x. Epub 2013 Sep 10.
To determine the influence of genetic polymorphisms on warfarin maintenance dose and to explicate an algorithm using the pharmacogenetic and clinical factors to determine the maintenance and/or starting dose of warfarin in South Indian patients receiving warfarin therapy.
Patients receiving stabilized warfarin therapy (n=257) were included in the study. Single nucleotide polymorphisms (SNPs) of CYP2C9 (rs1799853 and rs1057910), VKORC1 (rs9923231, rs7196161, rs2884737, rs9934438, rs8050894, rs2359612 and rs7294), CYP4F2 (rs2108622) and GGCX (rs11676382) were genotyped by the quantitative real time-PCR method.
The mean daily maintenance dose of warfarin was found to be 4.7 ± 2.1 mg/day. Patients with the CYP2C9*1/*2, *1/*3 and *2/3 variant genotypes required a 51.0 (2.8 mg), 60.9 (2.3 mg) and 62.2 % (2.2 mg) lower daily maintenance dose of warfarin, respectively, than those patients with the CYP2C91/*1 wild-type genotype (5.2 mg) (p<0.0001). The genetic variants of CYP2C9, VKORC1 and GGCX were associated with decreased warfarin dose, except for rs7196161, rs7294 and rs2108622 which were associated with an increased warfarin dose. Genetic variations of CYP2C9 (*2 and *3), VKORC1 (rs9923231, rs7294, rs9934438 and rs2359612), CYP4F2, GGCX and non-genetic factors such as age, body weight, clinical status (post mechanical valve replacement) could explain up to 62.1 % of the overall variation (adjusted r (2) 60.2 %, p<0.0001) in warfarin maintenance dose.
Genetic polymorphisms of CYP2C9, VKORC1, CYP4F2 and GGCX are important predictive factors of warfarin maintenance dose, and the developed algorithm will be useful to predict the required maintenance and/or starting warfarin dose in South Indian populations.
确定基因多态性对华法林维持剂量的影响，并阐明一种利用药物遗传学和临床因素来确定接受华法林治疗的南印度患者的维持剂量和/或起始剂量的算法。
本研究纳入了接受稳定华法林治疗的患者（n = 257）。采用定量实时聚合酶链反应方法对CYP2C9（rs1799853和rs1057910）、VKORC1（rs9923231、rs7196161、rs2884737、rs9934438、rs8050894、rs2359612和rs7294）、CYP4F2（rs2108622）和GGCX（rs11676382）的单核苷酸多态性进行基因分型。
发现华法林的平均每日维持剂量为4.7±2.1mg/天。与携带CYP2C9*1/1野生型基因型（5.2mg）的患者相比，携带CYP2C91/*2、*1/3和2/*3变异基因型的患者分别需要低51.0%（2.8mg）、60.9%（2.3mg）和62.2%（2.2mg）的华法林每日维持剂量（p<0.0001）。除rs7196161、rs7294和rs2108622与华法林剂量增加相关外，CYP2C9、VKORC1和GGCX的基因变异与华法林剂量降低相关。CYP2C9（2和3）、VKORC1（rs9923231、rs7294、rs9934438和rs2359612）、CYP4F2、GGCX的基因变异以及年龄、体重、临床状态（机械瓣膜置换术后）等非基因因素可解释华法林维持剂量总体变异的62.1%（调整后r² 60.2%，p<0.0001）。
CYP2C9、VKORC1、CYP4F2和GGCX的基因多态性是华法林维持剂量的重要预测因素，所开发的算法将有助于预测南印度人群所需的华法林维持剂量和/或起始剂量。
