Therapeutics and Clinical Risk Management (Mar 2017)

Polymorphisms of VKORC1 and CYP2C9 are associated with warfarin sensitivity in Chinese population

  • Jia LQ,
  • Wang Z,
  • Men J,
  • Cai H,
  • Wei M

Journal volume & issue
Vol. Volume 13
pp. 421 – 425

Abstract

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LiQun Jia,1 Zanxin Wang,1,2 Jianlong Men,3 Heng Cai,4 Minxin Wei2 1Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin, 2Department of Cardiac Surgery, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzhen, 3Department of Clinical Laboratory, 4Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China Objective: Warfarin is a commonly prescribed anticoagulant for prevention of thromboembolic events. Wide inter-individual dose variation, narrow therapeutic range and risk of serious bleeding result in difficulties in achieving the therapeutic effect. The present study was designed to clarify the real biological significance of the polymorphisms of VKORC1 and cytochrome P450 2C9 (CYP2C9) in warfarin metabolism.Methods: A total of 214 patients with warfarin anticoagulant therapy were selected. During follow-up of anticoagulation, warfarin dosage and associated international normalized ratio values were recorded. Genetic polymorphisms of VKORC1 promoter and from exon 1 to exon 3 and CYP2C9 exon 4 sequence were detected by polymerase chain reaction and gene sequencing.Results: Five polymorphisms were identified in this research, which were VKORC1 1173C>T (intron 1), 1542G>C (intron 2), 2255C>T (intron 2), 3730C>T (3'-downstream) and CYP2C9 exon 4 −65G>C. VKORC1 1173CT, 1542GC, 2255CT and 3730CT polymorphisms were detected in same patients, but CYP2C9 exon 4 −65GC carriers were different from them. VKORC1 1173CT, 1542GC, 2255CT, 3730CT carriers and CYP2C9 exon 4 −65GC carriers had significantly higher warfarin daily dosage than others (3.2±0.6 vs 3.1±1.1 vs 2.6±0.8 mg/day). Logistic regression analysis revealed VKORC1 1173CT, 1542GC, 2255CT, 3730CT carrier status (odds ratio [OR] =3.233, 95% confidence interval [CI]: 1.259–8.303, P=0.015) and obesity with body mass index >27 kg/m2 (OR =1.223, 95% CI: 1.097–1.363, P<0.001) to have independent and statistically significant contributions to high warfarin dosage.Conclusion: In general, in VKORC1 1173CT, 1542GC, 2255CT and 3730CT carriers and in obese patients, warfarin maintenance doses were significantly higher than in the others. Keywords: warfarin, vitamin K, cytochrome P450, polymorphism

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