Arunkumar Ganesan, Vishnuprabu Durairajpandian, Nupur Bitt, Vidyasagaran Thiruvengadam, Murugan Avaniyapuram Kannan, Munirajan Arasambattu Kannan
Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras.
Centre for Cardiovascular Biology and Disease (CCBD), Institute for Stem Cell Biology & Regenerative Medicine (inStem), National Center for Biological Sciences (NCBS), GKVK.
Drug Discov Ther. 2017;11(4):198-205. doi: 10.5582/ddt.2017.01031.
Deep vein thrombosis (DVT) is a life-threatening disease. Warfarin and acenocoumarol are anticoagulants used to treat DVT and vary among individuals in terms of treatment response/toxicity. Single nucleotide polymorphisms (SNPs) in CYP2C9 and VKORC1 play a role in the pharmacokinetics and dynamics of warfarin and acenocoumarol and they determine the efficacy of treatment by controlling drug clearance in treated individuals. The aim of the current study was to genotype the critical SNPs of CYP2C9 and VKORC1 genes in a south Indian population in order to understand the metabolizer phenotype of patients with DVT. CYP2C9 (rs1799853, rs1057910, rs1057909, rs28371686) and VKORC1 (rs9923231) SNPs were genotyped in 124 cases of DVT. Genomic regions of these SNPs from genomic DNA were amplified with PCR and directly sequenced using Sanger sequencing except for the SNP rs1799853, which was detected using Sau96I restriction endonuclease-based digestion of variant alleles. Among south Indian patients with DVT, 6.5% (8/124) had the rs1799853 SNP of CYP2C9 and 11% (14/124) had the rs1057910 SNP while 16% (20/124) had the rs9923231 SNP of VKORC1 which were associated with the response to warfarin treatment. None of the patients tested positive for poor drug metabolizing genotypes of the CYP2C9 gene and only 1.6% of the south Indian population was sensitive to warfarin treatment. Genotyping results suggest that a relatively greater amount of the therapeutic drug is required to achieve/maintain the international normalized ratio (INR) in south Indian patients with DVT.
深静脉血栓形成（DVT）是一种危及生命的疾病。华法林和醋硝香豆素是用于治疗DVT的抗凝剂，个体之间的治疗反应/毒性存在差异。细胞色素P450 2C9（CYP2C9）和维生素K环氧化物还原酶复合体1（VKORC1）中的单核苷酸多态性（SNP）在华法林和醋硝香豆素的药代动力学和药效学中起作用，它们通过控制治疗个体中的药物清除率来决定治疗效果。本研究的目的是对印度南部人群中CYP2C9和VKORC1基因的关键SNP进行基因分型，以了解DVT患者的代谢表型。对124例DVT患者的CYP2C9（rs1799853、rs1057910、rs1057909、rs28371686）和VKORC1（rs9923231）SNP进行了基因分型。除rs1799853 SNP外，这些SNP的基因组DNA区域通过聚合酶链反应（PCR）进行扩增，并使用桑格测序法直接测序，rs1799853 SNP通过基于Sau96I限制性内切酶的变异等位基因消化进行检测。在印度南部的DVT患者中，6.5%（8/124）具有CYP2C9的rs1799853 SNP，11%（14/124）具有rs1057910 SNP，而16%（20/124）具有VKORC1的rs9923231 SNP，这些与对华法林治疗的反应相关。没有患者的CYP2C9基因药物代谢不良基因型检测呈阳性，只有1.6%的印度南部人群对华法林治疗敏感。基因分型结果表明，在印度南部的DVT患者中，需要相对更多的治疗药物来达到/维持国际标准化比值（INR）。
