Sehgal Tushar, Hira Jasbir Kaur, Ahluwalia Jasmina, Das Reena, Vijayvergiya Rajesh, Rana Sandip Singh, Varma Neelam
Department of Hematology, Postgraduate Institute of Medical Education and Research.
Drug Discov Ther. 2015 Dec;9(6):404-10. doi: 10.5582/ddt.2015.01066.
Coumarin derivatives such as warfarin and acenocoumarol are used in various disorders such as deep venous thrombosis, pulmonary embolism, atrial fibrillation and artificial heart valves. They have improved prognosis of patients with thromboembolic disease. An individual's response to coumarins depends on several factors. The non-genetic factors include age, gender, body mass index, diet and interacting drugs. Among the genetic factors, the cytochrome P450 system and vitamin K epoxide reductase complex subunit 1 play a key role in drug metabolism. This was a prospective hospital based study in which allele and genotypic frequencies of CYP2C9 gene polymorphisms; 430C>T and 1075A>C and VKORC1 gene polymorphisms; 1639G>A, 9041G>A and 6009C>T in 106 alleles of north Indian patients with valve replacement on acenocoumarol were determined and their effect on acenocoumarol dosing was studied. To the best of our knowledge, this is first report of VKORC1 9041G>A and 6009C>T gene polymorphisms and their effect on acenocoumarol dosing from north India. In 53 patients with valve replacement on acenocoumarol with stable INR, the allele frequency of CYP2C92 and CYP2C93 gene polymorphisms was 0.05 and 0.17 respectively and that of VKORC1 2,3 and 4 gene polymorphisms was 0.15, 0.72 and 0.11 respectively. The presence of CYP2C93 or VKORC12 gene polymorphism were associated with decrease in acenocoumarol dose requirements (p values 0.03 and 0.02 respectively).This study confirmed the association of lower mean weekly dosages of acenocoumarol in patients with CYP2C93 and VKORC1*2 gene polymorphisms. An unusually high frequency of 9041A polymorphism in VKORC1 was found in study population.
香豆素衍生物如华法林和醋硝香豆素被用于多种疾病，如深静脉血栓形成、肺栓塞、心房颤动和人工心脏瓣膜。它们改善了血栓栓塞性疾病患者的预后。个体对香豆素的反应取决于几个因素。非遗传因素包括年龄、性别、体重指数、饮食和相互作用的药物。在遗传因素中，细胞色素P450系统和维生素K环氧化物还原酶复合物亚基1在药物代谢中起关键作用。这是一项基于医院的前瞻性研究，其中测定了106例接受醋硝香豆素治疗的北印度瓣膜置换患者等位基因和基因型频率，包括CYP2C9基因多态性（430C>T和1075A>C）以及VKORC1基因多态性（1639G>A、9041G>A和6009C>T），并研究了它们对醋硝香豆素剂量的影响。据我们所知，这是北印度关于VKORC1 9041G>A和6009C>T基因多态性及其对醋硝香豆素剂量影响的首次报告。在53例接受醋硝香豆素治疗且国际标准化比值（INR）稳定的瓣膜置换患者中，CYP2C92和CYP2C93基因多态性的等位基因频率分别为0.05和0.17，VKORC1 2、3和4基因多态性的等位基因频率分别为0.15、0.72和0.11。CYP2C93或VKORC12基因多态性的存在与醋硝香豆素剂量需求降低相关（p值分别为0.03和0.02）。本研究证实了CYP2C93和VKORC1*2基因多态性患者中醋硝香豆素平均每周剂量较低的相关性。在研究人群中发现VKORC1中9041A多态性的频率异常高。
