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European Journal of Clinical Pharmacology

, Volume 75, Issue 3, pp 343–350 | Cite as

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

  • Chanan Shaul
  • Simcha Blotnick
  • Liat Deutsch
  • Gilad Rosenberg
  • Yoseph CaracoEmail author
Pharmacogenetics
  • 107 Downloads

Abstract

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.

Keywords

Warfarin Genetic polymorphism R353Q Coagulation factor VII 

Notes

Acknowledgements

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

Funding information

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.

Supplementary material

228_2018_2594_MOESM1_ESM.pdf (29 kb)
ESM 1 S Warfarin concentration over time among carriers of CYP2C9*1/*1 (open squares) and CYP2C9*1/*2 or CYP2C9*1/*3 (closed squares) genotypes (PDF 29 kb)
228_2018_2594_MOESM2_ESM.pdf (28 kb)
ESM 2 R Warfarin concentration over time among carriers of CYP2C9*1/*1 (open squares) and CYP2C9*1/*2 or CYP2C9*1/*3 (closed squares) genotypes (PDF 28 kb)
228_2018_2594_MOESM3_ESM.pdf (24 kb)
ESM 3 INR over time among carriers of the CYP2C9*1/*1 (open circles) and CYP2C9*1/*2 or CYP2C9*1/*3 (closed circles) genotypes (PDF 24 kb)
228_2018_2594_MOESM4_ESM.pdf (25 kb)
ESM 4 INR over time among carriers of the VKORC1 BB (open circles), VKORC1 AB (crossed circles) and VKORC1 AA (closed circles) haplotypes (PDF 24 kb)
228_2018_2594_MOESM5_ESM.pdf (26 kb)
ESM 5 Factor VII activity over time among carriers of the CYP2C9*1/*1 (open squares) and CYP2C9*1/*2 or CYP2C9*1/*3 (closed squares) genotypes (PDF 26 kb)
228_2018_2594_MOESM6_ESM.pdf (27 kb)
ESM 6 Factor VII activity over time among carriers of the VKORC1 BB (open squares), VKORC1 AB (crossed squares) and VKORC1 AA (closed squares) haplotypes (PDF 27 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Clinical Pharmacology Unit, Division of MedicineHadassah-Hebrew University Medical CenterJerusalemIsrael
  2. 2.Institute of Drug Research, School of Pharmacy, Faculty of MedicineHebrew UniversityJerusalemIsrael
  3. 3.D-Pharm Ltd.RehovotIsrael

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