Dataset Information

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

ABSTRACT: 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.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.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.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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5006145 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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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.

Zhang Jinhua J Chen Zhijie Z Chen Chunmei C

Meta gene 20160705

<h4>Introduction</h4>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.<h4>Methods</h4>Strict literature inclusion criteria were established, and literature searching was performed on PubMed, Embase and Cochrane Library for English articles and CNKI, C ...[more]

PMID: 27617219

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Project description:BackgroundWarfarin is the most recommended oral anticoagulant after artificial mechanical valve replacement therapy. However, the narrow therapeutic window and varying safety and efficacy in individuals make dose determination difficult. It may cause adverse events such as hemorrhage or thromboembolism. Therefore, advanced algorithms are urgently required for the use of warfarin.ObjectiveTo establish a warfarin dose model for patients after prosthetic mechanical valve replacement in southern China in combination with clinical and genetic variables, and to improve the accuracy and ideal prediction percentage of the model.MethodsClinical data of 476 patients were tracked and recorded in detail. The gene polymorphisms of VKORC1 (rs9923231, rs9934438, rs7196161, and rs7294), CYP2C9 (rs1057910), CYP1A2 (rs2069514), GGCX (rs699664), and UGT1A1 (rs887829) were determined using Sanger sequencing. Multiple linear regressions were used to analyze the gene polymorphisms and the contribution of clinical data variables; the variables that caused multicollinearity were screened stepwise and excluded to establish an algorithm model for predicting the daily maintenance dose of warfarin. The ideal predicted percentage was used to test clinical effectiveness.ResultsA total of 395 patients were included. Univariate linear regression analysis suggested that CYP1A2 (rs2069514) and UGT1A1 (rs887829) were not associated with the daily maintenance dose of warfarin. The new algorithm model established based on multiple linear regression was as follows: Y = 1.081 - 0.011 (age) + 1.532 (body surface area)-0.807 (rs9923231 AA) + 1.788 (rs9923231 GG) + 0.530 (rs1057910 AA)-1.061 (rs1057910 AG)-0.321 (rs699664 AA). The model accounted for 61.7% of individualized medication differences, with an ideal prediction percentage of 69%.ConclusionGGCX (rs699664) may be a potential predictor of warfarin dose, and our newly established model is expected to guide the individualized use of warfarin in clinical practice in southern China.

Project description:BackgroundWarfarin is a highly effective anticoagulant however its effectiveness relies on maintaining INR in therapeutic range. Finding the correct dose is difficult due to large inter-individual variability. Two genes, CYP2C9 and VKORC1, have been associated with this variability, leading to genotype-guided dosing tables in warfarin labeling. Nonetheless, it remains unclear how genotypic information should be used in practice. Navigating the literature to determine how genotype will influence warfarin response in a particular patient is difficult, due to significant variation in patient ethnicity, outcomes investigated, study design, and methodological rigor. Our systematic review was conducted to enable fair and accurate interpretation of which variants affect which outcomes, in which patients, and to what extent.Methodology/principal findingsA comprehensive search strategy was applied and 117 studies included. Primary outcomes were stable dose, time to stable dose and bleeding events. Methodological quality was assessed using criteria of Jorgensen and Williamson and data synthesized in meta-analyses using advanced methods. Pooled effect estimates were significant in most ethnic groups for CYP2C9*3 and stable dose (mutant types requiring between 1.1(0.7-1.5) and 2.3 (1.6-3.0)mg/day). Effect estimates were also significant for VKORC1 and stable dose for most ethnicities, although direction differed between asians and non-asians (mutant types requiring between 0.8(0.4-1.3) and 1.5(1.1-1.8)mg/day more in asians and between 1.5(0.7-2.2) and 3.1(2.7-3.6)mg/day less in non-asians). Several studies were excluded due to inadequate data reporting. Assessing study quality highlighted significant variability in methodological rigor. Notably, there was significant evidence of selective reporting, of outcomes and analysis approaches.Conclusions/significanceGenetic associations with warfarin response vary between ethnicities. In order to achieve unbiased estimates in different populations, a high level of methodological rigor must be maintained and studies should report sufficient data to enable inclusion in meta-analyses. We propose minimum reporting requirements, suggest methodological guidelines and provide recommendations for reducing the risk of selective reporting.

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Dataset Information

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

Publications

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

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