The impact of R353Q genetic polymorphism in coagulation factor VII on the initial anticoagulant effect exerted by warfarin

• Published in: European journal of clinical pharmacology Vol. 75; no. 3; pp. 343 - 350
• Main Authors: Shaul, Chanan, Blotnick, Simcha, Deutsch, Liat, Rosenberg, Gilad, Caraco, Yoseph
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2019; Springer Nature B.V
• Subjects: Adult; Anticoagulants; Anticoagulants - administration & dosage; Anticoagulants - blood; Arginine - genetics; Biomedical and Life Sciences; Biomedicine; Blood Coagulation - genetics; Cholesterol; Coagulation; Coagulation factor VII; Coagulation factors; Cytochrome P-450 CYP2C9 - genetics; Drug Monitoring; Factor VII - analysis; Gene polymorphism; Genetic diversity; Genotype; Glutamine - genetics; Humans; International Normalized Ratio; Linear Models; Male; Multiple regression analysis; Multivariate Analysis; Pharmacogenetics; Pharmacology/Toxicology; Polymorphism; Polymorphism, Single Nucleotide; Vitamin K Epoxide Reductases - genetics; Warfarin; Warfarin - administration & dosage; Warfarin - blood; Young Adult; Coagulation factor VII; Warfarin; Genetic polymorphism; R353Q
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-018-2594-2

Background The initial rise in INR following warfarin is attributed to rapid decline in coagulation factor VII (F7). The R353Q polymorphism in F7 accounts for approximately 1/3 of the variability in F7 activity (FVIIc). Objective Evaluate the role of R353Q in the initial response to warfarin. Methods Twenty-eight healthy, males, carrying CYP2C9*1/*1 ( n  = 14), CYP2C9*1/*2 ( n  = 4) or CYP2C9*1/*3 ( n  = 10) genotypes, received single 20 mg warfarin. S&R- warfarin concentrations, INR, and FVIIc were monitored periodically for 7 days. Results Baseline and maximal INR were 5.6% and 33.5% higher among carriers of the RQ ( n  = 12) as compared with those carrying the RR ( n  = 16) genotype ( p  = 0.032, p  = 0.003, respectively). Baseline and nadir FVIIc were 21.6% and 42.0% lower among subjects carrying the RQ as compared with carriers of the RR genotype ( p  = 0.001, p  = 0.007 respectively). In multiple regression analysis, R353Q predicted 36.6% of the variability in peak INR whereas 20.2%, 9.9%, and 5.9% were attributed to VKORC1 genetic polymorphism, cholesterol concentration, and S Warfarin concentration after 24 h, respectively. Conclusions R353Q genetic polymorphism plays a key role in determining the initial response to warfarin. The incorporation of this genetic variant into warfarin loading algorithm should be further investigated.