No association between vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) and the variability of warfarin dose requirement in a Japanese patient population

Abstract Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

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Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements

Clinical Pharmacology & Therapeutics ◽

10.1016/j.clpt.2005.11.011 ◽

2006 ◽

Vol 79 (4) ◽

pp. 291-302 ◽

Cited By ~ 203

Author(s):

C AQUILANTE ◽

T LANGAEE ◽

L LOPEZ ◽

H YARANDI ◽

J TROMBERG ◽

...

Keyword(s):

Cytochrome P450 ◽

Vitamin K ◽

Gene Polymorphisms ◽

Warfarin Dose ◽

Coagulation Factor ◽

Cytochrome P450 2C9 ◽

Vitamin K Epoxide Reductase ◽

Epoxide Reductase

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Multiple genetic alterations in vitamin K epoxide reductase complex subunit 1 gene (VKORC1) can explain the high dose requirement during oral anticoagulation in humans

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2008.03049.x ◽

2008 ◽

Vol 6 (8) ◽

pp. 1436-1439 ◽

Cited By ~ 26

Author(s):

L. BODIN ◽

J. PERDU ◽

M. DIRY ◽

M.-H. HORELLOU ◽

M.-A. LORIOT

Keyword(s):

Vitamin K ◽

Oral Anticoagulation ◽

Genetic Alterations ◽

High Dose ◽

Dose Requirement ◽

Vitamin K Epoxide Reductase ◽

Epoxide Reductase

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Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1

Thrombosis and Haemostasis ◽

10.1160/th04-08-0540 ◽

2005 ◽

Vol 93 (01) ◽

pp. 23-26 ◽

Cited By ~ 86

Author(s):

Dominic Harrington ◽

Sarah Underwood ◽

Colin Morse ◽

Martin Shearer ◽

Edward Tuddenham ◽

...

Keyword(s):

Vitamin K ◽

Dose Response ◽

Reductase Activity ◽

Warfarin Dose ◽

Coagulation Factor ◽

Gene Encoding ◽

Vitamin K Epoxide Reductase ◽

Epoxide Reductase ◽

Undetectable Serum ◽

Warfarin Resistance

SummaryThe gene encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), a component of the enzyme that is the therapeutic target site for warfarin, has recently been identified. In order to investigate the relationship betweenVKORC1 and warfarin dose response, we studied theVKORC1 gene (VKORC1) in patients with warfarin resistance. From a study group of 820 patients, we identified 4 individuals who required more than 25 mg of warfarin daily for therapeutic anticoagulation.Three of these had serum warfarin concentrations within the therapeutic range of 0.7–2.3 mg/l and showed wild-type VKORC1 sequence. The fourth warfarin resistant individual had consistently high ( ≥ 5.7 mg/l) serum warfarin concentrations, yet had no clinically discernible cause for warfarin resistance. VKORC1 showed a heterozygous 196G→ A transition that predicted aVal66Met substitution in the VKORC1 polypeptide. This transition was also identified in 2 asymptomatic family members who had never received warfarin.These individuals had normal vitamin-K dependent coagulation factor activities and undetectable serum PIVKAII and vitamin K 1 2,3 epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORC1 Val66Met substitution.The association between a nucleotide transition in VKORC1 and pharmacodynamic warfarin resistance supports the hypothesis that VKORC1 is the site of action of warfarin and indicates that VKORC1 sequence is an important determinant of the warfarin dose response.

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Validation of Pharmacogenetic Testing Before Initiation of Warfarin Therapy

University Heart Journal ◽

10.3329/uhj.v15i2.42665 ◽

2019 ◽

Vol 15 (2) ◽

pp. 74-78

Author(s):

MSI Tipu Chowdhury ◽

Md Fakhrul Islam Khaled ◽

Sadia Sultana ◽

Mohammad Walidur Rahman ◽

MRM Mandal ◽

...

Keyword(s):

Vitamin K ◽

Warfarin Therapy ◽

Warfarin Dose ◽

Bleeding Complications ◽

Fixed Dose ◽

Vitamin K Epoxide Reductase ◽

International Normalization Ratio ◽

Cytochrome 450 ◽

Epoxide Reductase ◽

Cardiac Valve Replacement

Warfarin is an oral anticoagulant used to prevent or treat clotting disorders associated with venous thrombosis, pulmonary embolism, atrial fibrilation, cardiac valve replacement, stroke and acute myocardial infarction. It is a vitamin K antagonist composed of S- and R- isomers. The more potent S-warfarin is metabolized by cytochrome 450 isoenzyme 2C9 (CYP2C9), encoded by CYP2C9 gene. Warfarin exerts its anticoagulants effect by inhibitingits target enzyme vitamin K epoxide reductase (VKOR), encoded by vitamin K epoxide reductase subunit 1 (VKOR1) gene. Genetic variation in the CYP2C9 and VKOR1 gene can affect warfarin efficacy and dose required to achieve stable International Normalization Ratio (INR). Specifically two variants in the CYP2CP gene (CYP2C9*2 and CYP2C9*3) result in an enzyme with reduced activity, leading to increased active warfarin levels. A variant in the VKORC1 gene (VKORC1-1639 G>A) can lead to reduced gene expression resulting in decresed level of VKOR. Together these three variants can account for 40-70% of the variability of warfarin dose. Carriers of variant alleles are at higher risk for bleeding complications, particularly at the induction of warfarin therapy. So, genotype-guided dosing algorithms would be better approximate for maintenance of warfarin dose than fixed-dose algorithms. University Heart Journal Vol. 15, No. 2, Jul 2019; 74-78

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Abstract 1810: Vitamin K Epoxide Reductase Complex Subunit 1 (vkorc1) Gene Polymorphism is Associated with Atherothrombotic Complication after Drug-Eluting Stent Implantation : Two Center Prospective Cohort Study

Circulation ◽

10.1161/circ.118.suppl_18.s_390-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Jung-Won Suh ◽

Jin-Shik Park ◽

Hyun-Jae Kang ◽

In-Ho Chae ◽

Dong-Ju Choi ◽

...

Keyword(s):

Clinical Outcomes ◽

Vitamin K ◽

Cardiovascular Events ◽

Warfarin Dose ◽

Drug Eluting Stent ◽

Free Survival ◽

Vitamin K Epoxide Reductase ◽

Cox Regression Analysis ◽

Epoxide Reductase ◽

Drug Eluting

Single nucleotide polymorphisms (SNPs) of Vitamin K epoxide reductase complex subunit 1 (VKORC1) affect warfarin dose response. Recently, SNP of VKORC1 +2255 was reported to have association with arterial vascular disease. However, it is not known whether SNP of VKORC1 affects clinical outcomes among patients who underwent drug-eluting stent (DES) implantation. We prospectively collected genomic DNA in patients who underwent DES deployment from Sep 2003 to Dec 2006 and compared clinical outcomes according to their VKORC1 genotype. The primary end-point was composite of atherothrombotic events [cardiac death, myocardial infarction, and non-hemorrhagic stroke]. Mean follow-up duration was 631±251 days. Genotyping was completed in 764 cases (TT genotype (n=640, 83.8%) vs. non-TT (CC or CT) genotype (n=124, 16.2%)). Non-TT group showed more composite events events than TT group (7.3% vs, 3.0%, p=0.032). In the Cox regression analysis, non-TT genotype of VKORC gene was a significant predictor of atherothrombotic events (Hazard ratio 2.56, 95% confidence interval 1.14±5.78). In the event-free survival analysis, non-TT group also showed significantly poorer cardiovascular events-free survival rate than TT group (p=0.02). VKORC1 genotype is associated with cardiovascular events in patients with DES implantation, suggesting the role of coagulation system.

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