Effect of VKORC1 – 1639 G > A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients

• Published in: Thrombosis research Vol. 124; no. 2; pp. 161 - 166
• Main Authors: Yoshizawa, Misa, Hayashi, Hideki, Tashiro, Yoshio, Sakawa, Sonoko, Moriwaki, Hideaki, Akimoto, Takehide, Doi, Osamu, Kimura, Midori, Kawarasaki, Yoshinori, Inoue, Kazuyuki, Itoh, Kunihiko
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2009; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Algorithms; Alleles; Anticoagulants - administration & dosage; Anticoagulants - therapeutic use; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Blood and lymphatic vessels; Blood. Blood coagulation. Reticuloendothelial system; Body Weight - genetics; Cardiology. Vascular system; CYP2C9; Cytochrome P-450 CYP2C9; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dosing algorithm; Female; Gene Frequency; Genetic polymorphisms; Genotype; Hematology, Oncology and Palliative Medicine; Humans; Japan - epidemiology; Linear Models; Male; Medical sciences; Middle Aged; Mixed Function Oxygenases - genetics; Pharmacology. Drug treatments; Polymorphism, Genetic; Retrospective analysis; Retrospective Studies; Serum Albumin - genetics; Vitamin K Epoxide Reductases; VKORC1; Warfarin; Warfarin - administration & dosage; Warfarin - therapeutic use; VKORC1; FDA; Warfarin; Retrospective analysis; PCR-RFLP; Genetic polymorphisms; Dosing algorithm; CYP2C9; ANCOVA; SNP; GGCX; ANOVA; V max; MD; K m; PT-INR; single nucleotide polymorphism; maintenance dose; analysis of variance; Cytochrome P450 2C9; polymerase chain reaction-restriction fragment length polymorphism; Food and Drug Administration; γ-glutamylcarboxylase; prothrombin time normalized as an international normalized ratio; Michaelis constant; maximum velocity; Vitamin K epoxide reductase complex subunit 1; analysis of covariance; Human; Coumarine derivatives; Body weight; Albumin; Cardiovascular disease; Anticoagulant; Japanese; Antivitamin K; Polymorphism
• ISSN: 0049-3848; 1879-2472; 1879-2472
• DOI: 10.1016/j.thromres.2008.11.011

To establish individualized warfarin therapy, we investigated the contribution of genetic variations of vitamin K epoxide reductase complex subunit 1 gene ( VKORC1) – 1639 G > A and Cytochrome P450 2C9 gene ( CYP2C9) and clinical factors on warfarin sensitivity in Japanese patients. Genetic analyses of VKORC1 – 1639 G > A and CYP2C9 ⁎2, ⁎3, and ⁎4 were performed in 259 Japanese patients and 341 healthy subjects. We selected 259 patients who have been prescribed warfarin with a 1.5–3.0 range of prothrombin time normalized as an international normalized ratio for at least 3 months and investigated factors that contribute to individual variability in warfarin dose. Furthermore, multivariate analysis was performed to investigate a warfarin dosing algorithm. There were great inter-individual differences in warfarin maintenance dose in 259 patients, ranging from a minimum dose of 0.75 mg/day to a maximal dose of 8.00 mg/day. VKORC1 – 1639 G > A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variability. The dosing algorithm of warfarin maintenance dose was investigated by multivariate linear regression. The regression equation was able to account for 33.2% (R 2 Adj = 0.332) of the overall variability in warfarin dose.