The impact of R353Q genetic polymorphism in coagulation factor VII on the initial anticoagulant effect exerted by warfarin
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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).
Evaluate the role of R353Q in the initial response to warfarin.
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.
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.
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.
KeywordsWarfarin Genetic polymorphism R353Q Coagulation factor VII
Trial registration: Clinicaltrials.gov Identifier NCT00162435
Dr. Chanan Shaul is a Ph.D. student at the Hebrew University of Jerusalem under the supervision of Prof. Yoseph Caraco. This work was done as a partial fulfillment for the requirements of Dr. Chanan Shaul’s Ph.D. thesis degree at the Hebrew-University of Jerusalem, Israel.
Contribution of authors statement
Chanan Shaul - Contributed to conception and design of the study, took part in data acquisition, analysis and interpretation, and played a substantial role in drafting the manuscript
Simcha Blotnick - Contributed to data acquisition, analysis, and interpretation
Liat Deutsch - Contributed to conception and design of the study as well as to data acquisition, analysis, and interpretation
Gilad Rosenberg - Contributed to data acquisition, analysis, and interpretation and took active part in drafting the manuscript
Yoseph Caraco – Was the initiator of the study, took active part in data acquisition, analysis and interpretation and drafting the manuscript
The study was supported by a grant from the Bi-national US–Israel Science Foundation (YC) and a grant from the Israeli Science Foundation (YC), Jerusalem, Israel.
Compliance with ethical standards
Conflict of interest
Chanan Shaul declares no conflicts of interest.
Simcha Blotnick declares no conflicts of interest.
Liat Mlynarsky declares no conflicts of interest.
Gilad Rosenberg was an employee of D-Pharm. Ltd. at the time of study conduct. D-Pharm. Ltd. sponsored the original study that investigated possible interaction between DP-b99 and warfarin (publication # 23 in the reference list).
Yoseph Caraco declares no conflicts of interest.
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