Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy.

AIMS We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. MATERIALS & METHODS In total, 982 warfarin-treated patients from the RE-LY trial were studied. RESULTS After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R(2) by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. CONCLUSIONS We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.

[1]  D. Singer,et al.  Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry. , 2015, American heart journal.

[2]  A. Wu.  Pharmacogenomic testing and response to warfarin , 2015, The Lancet.

[3]  E. Antman,et al.  Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial , 2015, The Lancet.

[4]  Munir Pirmohamed,et al.  A Randomized Trial of Genotype-Guided Dosing of Warfarin , 2014 .

[5]  N. Eriksson,et al.  A randomized trial of genotype-guided dosing of warfarin. , 2013, The New England journal of medicine.

[6]  R. Califf,et al.  A pharmacogenetic versus a clinical algorithm for warfarin dosing. , 2013, The New England journal of medicine.

[7]  G. Lip,et al.  Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT₂R₂ score. , 2013, Chest.

[8]  J. Jespersen,et al.  The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment. , 2013, Thrombosis research.

[9]  S. Yusuf,et al.  Variation in Warfarin Dose Adjustment Practice Is Responsible for Differences in the Quality of Anticoagulation Control Between Centers and Countries: An Analysis of Patients Receiving Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial , 2012, Circulation.

[10]  Niclas Eriksson,et al.  Prediction of warfarin dose: why, when and how? , 2012, Pharmacogenomics.

[11]  O. Delaneau,et al.  A linear complexity phasing method for thousands of genomes , 2011, Nature Methods.

[12]  J. Marchini,et al.  Genotype Imputation with Thousands of Genomes , 2011, G3: Genes | Genomes | Genetics.

[13]  N. Chaiyakunapruk,et al.  Assessing evidence of interaction between smoking and warfarin: a systematic review and meta-analysis. , 2011, Chest.

[14]  Gregory Y H Lip,et al.  Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. , 2011, Journal of the American College of Cardiology.

[15]  A. Camm,et al.  Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). , 2010, European heart journal.

[16]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[17]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[18]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[19]  S. Yusuf,et al.  Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. , 2009, American heart journal.

[20]  Nicole Soranzo,et al.  A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose , 2009, PLoS genetics.

[21]  R. Altman,et al.  Estimation of the warfarin dose with clinical and pharmacogenetic data. , 2009, The New England journal of medicine.

[22]  Panos Deloukas,et al.  The largest prospective warfarin-treated cohort supports genetic forecasting. , 2009, Blood.

[23]  M. Rieder,et al.  Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin , 2008, Clinical pharmacology and therapeutics.

[24]  M. Rieder,et al.  A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. , 2008, Blood.

[25]  Y. Turpaz,et al.  CYP4F2 genetic variant alters required warfarin dose. , 2008, Blood.

[26]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[27]  M. Aguilar,et al.  Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation , 2007, Annals of Internal Medicine.

[28]  Yurii S. Aulchenko,et al.  BIOINFORMATICS APPLICATIONS NOTE doi:10.1093/bioinformatics/btm108 Genetics and population analysis GenABEL: an R library for genome-wide association analysis , 2022 .

[29]  P. Deloukas,et al.  Association of warfarin dose with genes involved in its action and metabolism , 2006, Human Genetics.

[30]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[31]  Deborah A Nickerson,et al.  Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. , 2005, The New England journal of medicine.

[32]  S. Hunt,et al.  Common VKORC1 and GGCX polymorphisms associated with warfarin dose , 2005, The Pharmacogenomics Journal.

[33]  Valentin Fuster,et al.  AHA/ACC Scientific StatementAmerican Heart Association/American College of Cardiology Foundation guide to warfarin therapy1 , 2003 .

[34]  Valentin Fuster,et al.  American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. , 2003, Circulation.

[35]  M. Rich,et al.  Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. , 2001, JAMA.

[36]  D. Sackett,et al.  The number needed to treat: a clinically useful measure of treatment effect , 1995, BMJ.

[37]  F R Rosendaal,et al.  A Method to Determine the Optimal Intensity of Oral Anticoagulant Therapy , 1993, Thrombosis and Haemostasis.