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      • Record: found
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      Impact of CYP2C9, VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients: A systematic review and meta-analysis

      review-article
      Author(s): a , 1 , b , 1 , b , *
      Publication date (Electronic):
      Journal: Meta Gene
      Publisher: Elsevier
      Keywords: INR, International Normalized Ratio, CYP2C9, Cytochrome P450 Complex Subunit 2C9, CYP4F2, Cytochrome P450 Complex Subunit 4F2, VKORC1, Vitamin K Epoxide Reductase Complex Subunit 1, SNPs, Single Nucleotide Polymorphisms, MDWD, Mean Daily Warfarin Dose, CI, Confidence Interval, MD, Mean Difference, SD, Standard Deviation, VTE, Venous Thromboembolism, AF, Atrial Fibrillation, DVT, Deep Vein Thrombosis, AVR, Atrial Valve Replacement, HVR, Heart Valve Replacement, MHVR, Mechanical Heart Valve Replacement, MVR, Mitral Valve Replacement, PE, Pulmonary Embolism, RHD, Rheumatic Heart Disease, NVAF, Non Valvular Atrial Fibrillation, Warfarin, Han-Chinese, Meta-analysis, CYP2C9, VKORC1

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          Abstract

          Introduction

          Warfarin is the most commonly used antithrombotic drug. Single nucleotide polymorphisms (SNPs) of CYP2C9, CYP4F2, VKORC1 1173 and VKORC1-1639 influence warfarin maintenance dosage. We aimed to determine the impact of SNPs of these genes on mean daily warfarin dosage (MDWD) in Han-Chinese patients.

          Methods

          Strict literature inclusion criteria were established, and literature searching was performed on PubMed, Embase and Cochrane Library for English articles and CNKI, CBM and Wanfang database for Chinese articles before September 2, 2014. Revman 5.3 was used to analyze the relationship between gene SNPs and MDWD in Han-Chinese subjects.

          Results

          We included 33 studies researching the impact of gene SNPs on MDWD in Han-Chinese subjects. CYP2C9 *3/*3, *1/*3 and *3 carriers needed a 72% (95% confidence interval [CI]: 62.0%–81.0%), 28% (22.0%–33.0%) and 26% (21.0%–32.0%) lower MDWD, respectively, than CYP2C9 *1/*1 carriers. CYP4F2 TT, CT and T carriers required a 18% (7.0%–30.0%), 7% (7.0%–7.0%) and 11% (7.0%–14.0%) higher MDWD, respectively, than CYP4F2 CC carriers. VKORC1 1173 CC, CT and C carriers required a 98% (78.0%–118.0%), 49% (37.0%–62.0%) and 56% (44.0%–67.0%) higher MDWD, respectively, than VKORC1 1173 TT carriers. VKORC1-1639 GG, GA and G carriers needed a 101% (53.0%–149.0%), 40% (36.0%–45.0%) and 38% (35.0%–42.0%) higher MDWD, respectively, than VKORC1-1639 AA carriers.

          Conclusions

          This meta-analysis is the first to report the relationship between genotypes and MDWD among Han-Chinese patients. The results showed that SNPs of CYP2C9, CYP4F2, VKORC1 1173 and VKORC1-1639 significantly influenced the MDWD in Han-Chinese patients.

          Highlights

          • •

            This meta-analysis examined the effects of genotype on mean daily warfarin dosage.

          • •

            CYP2C9, CYP4F2 and VKORC1 genotypes were studied in Han-Chinese patients.

          • •

            CYP2C9, CYP4F2, VKORC1-1173 and VKORC1-1639 polymorphisms affected warfarin dosage.

          • •

            VKORC1-1173 C and VKORC1-1639 G mutations had similar frequencies and effects.

          • •

            Either genotype can be tested for to guide drug usage and lower medical costs.

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          Most cited references67

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          Molecular basis of ethnic differences in drug disposition and response.

          Catherine M Stein, Ira Kim, H Xie … (2000)
          Ethnicity is an important demographic variable contributing to interindividual variability in drug metabolism and response. In this rapidly expanding research area many genetic factors that account for the effects of ethnicity on pharmacokinetics, pharmacodynamics, and drug safety have been identified. This review focuses on recent developments that have improved understanding of the molecular mechanisms responsible for such interethnic differences. Genetic variations that may provide a molecular basis for ethnic differences in drug metabolizing enzymes (CYP 2C9, 2C19, 2D6, and 3A4), drug transporter (P-glycoprotein), drug receptors (adrenoceptors), and other functionally important proteins (eNOS and G proteins) are discussed. A better understanding of the molecular basis underlying ethnic differences in drug metabolism, transport, and response will contribute to improved individualization of drug therapy.
          Article 0 comments Cited 86 times – based on 0 reviews     Review now
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            The largest prospective warfarin-treated cohort supports genetic forecasting.

            Ralph McGinnis, Panos Deloukas, Anders Rane … (2009)
            Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.
            Article 0 comments Cited 80 times – based on 0 reviews     Review now
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              A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.

              Min-Ji Charng, Ya-Chi Hung, M T Michael Lee … (2005)
              Warfarin, a commonly prescribed anticoagulant, exhibited large inter-individual and inter-ethnic differences in the dose required for its anticoagulation effect. Asian populations, including Chinese, require a much lower maintenance dose than Caucasians, for which the mechanisms still remain unknown. We determined DNA sequence variants in CYP2C9 and VKORC1 in 16 Chinese patients having warfarin sensitivity ( or = 6.0 mg/day, n = 5), 104 randomly selected Chinese patients receiving warfarin, 95 normal Chinese controls and 92 normal Caucasians. We identified three CYP2C9 variants, CYP2C9*3, T299A and P382L, in four warfarin-sensitive patients. A novel VKORC1 promoter polymorphism (-1639 G > A) presented in the homozygous form (genotype AA) was found in all warfarin-sensitive patients. The resistant patients were either AG or GG. Among the 104 randomly selected Chinese patients receiving warfarin, AA genotype also had lower dose than the AG/GG genotype (P < 0.0001). Frequencies of AA, AG and GG genotypes were comparable in Chinese patients receiving warfarin (79.7, 17.6 and 2.7%) and normal Chinese controls (82, 18 and 0%), but differed significantly from Caucasians (14, 47 and 39%) (P < 0.0001). The promoter polymorphism abolished the E-box consensus sequences and dual luciferase assay revealed that VOKRC1 promoter with the G allele had a 44% increase of activity when compared with the A allele. The differences in allele frequencies of A/G allele and its levels of VKORC1 promoter activity may underscore the inter-individual differences in warfarin dosage as well as inter-ethnic differences between Chinese and Caucasians.
              Article 0 comments Cited 76 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Chunmei Chen
                Journal
                Journal ID (nlm-ta): Meta Gene
                Journal ID (iso-abbrev): Meta Gene
                Title: Meta Gene
                Publisher: Elsevier
                ISSN (Electronic): 2214-5400
                Publication date PMC-release: 05 July 2016
                Publication date Collection: September 2016
                Publication date (Electronic): 05 July 2016
                Volume: 9
                Pages: 197-209
                Affiliations
                [a ]Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou 350001, PR China
                [b ]Department of Neurosurgery, Fujian Medical University Union Hospital, Fuzhou 350001, PR China
                Author notes
                [* ]Corresponding author. pollyzhang2006@ 123456126.com
                [1]

                Jinhua Zhang and Zhijie Chen contributed equally to this paper.

                Article
                Publisher ID: S2214-5400(16)30025-1
                DOI: 10.1016/j.mgene.2016.07.002
                PMC ID: 5006145
                PubMed ID: 27617219
                SO-VID: e29bede0-9b66-414f-888d-d315cdf243fa
                Copyright © © 2016 Elsevier B.V. All rights reserved.
                History
                Date received : 25 December 2015
                Date revision received : 4 July 2016
                Date accepted : 4 July 2016
                Categories
                Subject: Article

                Keywords: inr, international normalized ratio,cyp2c9, cytochrome p450 complex subunit 2c9,cyp4f2, cytochrome p450 complex subunit 4f2,vkorc1, vitamin k epoxide reductase complex subunit 1,snps, single nucleotide polymorphisms,mdwd, mean daily warfarin dose,ci, confidence interval,md, mean difference,sd, standard deviation,vte, venous thromboembolism,af, atrial fibrillation,dvt, deep vein thrombosis,avr, atrial valve replacement,hvr, heart valve replacement,mhvr, mechanical heart valve replacement,mvr, mitral valve replacement,pe, pulmonary embolism,rhd, rheumatic heart disease,nvaf, non valvular atrial fibrillation,warfarin,han-chinese,meta-analysis,cyp2c9,vkorc1
                Data availability:
                Keywords: inr, international normalized ratio, cyp2c9, cytochrome p450 complex subunit 2c9, cyp4f2, cytochrome p450 complex subunit 4f2, vkorc1, vitamin k epoxide reductase complex subunit 1, snps, single nucleotide polymorphisms, mdwd, mean daily warfarin dose, ci, confidence interval, md, mean difference, sd, standard deviation, vte, venous thromboembolism, af, atrial fibrillation, dvt, deep vein thrombosis, avr, atrial valve replacement, hvr, heart valve replacement, mhvr, mechanical heart valve replacement, mvr, mitral valve replacement, pe, pulmonary embolism, rhd, rheumatic heart disease, nvaf, non valvular atrial fibrillation, warfarin, han-chinese, meta-analysis, cyp2c9, vkorc1

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