EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD00010000704714EGA dataset EGAD00010000704EGA<h4>Background</h4>Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin.<h4>Methods</h4>A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R.<h4>Results</h4>VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role.<h4>Conclusion</h4>Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.A multi-factorial analysis of response to warfarin in a UK prospective cohort.Bourgeois Stephane S, Jorgensen Andrea A, Zhang Eunice J EJ, Hanson Anita A, Gillman Matthew S MS, Bumpstead Suzannah S, Toh Cheng Hock CH, Williamson Paula P, Daly Ann K AK, Kamali Farhad F, Deloukas Panos P, Pirmohamed Munir MCoumadin response, assay, response to Coumadin., determination, chemical analysisImputed, Imputation, Impute, Statistical Imputation.4-hydroxy-3-[(1RS)-3-oxo-1-phenylbutyl]-2H-chromen-2-one, Product, Anticoagulation, determination, warfarina, 4-hydroxy-3-[(1RS)-3-oxo-1-phenylbutyl]coumarin, P450 MP-4, warfarine, P450 MP-8, Normalized Ratio, height, Techniques, International Normalized Ratios, Roles, Method, responsivity, Pharmaceutical Product, Concepts, Inhibitors, Aldocumar, pale/ple, MST134, 2310040B03Rik, warfarinum, Inr-alpha, Anticoagulant, Genomes, (+-)-warfarin, Chip, ChIP, Alcohol Drinking Habits, hypoplasia, CHIP, Drinking Habit, procedures, broad., insulin/insulin-like growth factor receptor, genetic, chip, InsR, Cytochrome P450, Methodological Studies, 2H-1-Benzopyran-2-one, medicine, Pharmaceutical, DIR, (RS)-warfarin, Role Concepts, DIHR, AW046544, CYP2C9, Coumadine, TH, DmelCG18402, rac-4-hydroxy-3-(3-oxo-1-phenylbutyl)coumarin, l(2)k04405, wide/broad, l(3)93Dj, Alcohol, Index, dir, dIR, Alcohol Drinking Habit, Cytochrome P450 MP-8, familial, Ratios, DmelCG10118, Th, Procedure, EDTP308, Cytochrome P450 MP-4, results, Inr-beta, Brumolin, rac-3-(1'-phenyl-2'-acetylethyl)-4-hydroxycoumarin, Role Concept, weight, MP-8, RENBP, MP-4, Cytochrome P 450 CYP2C9, Role, Warfant, Pharmaceutic, Kumatox, SDCCAG7, Smoking, tobacco use disorder, clotting, dInr, dINR, dLdb, DInR, Normalized Ratios, common, Ratron, whole genome, Methodological, IMAGE3455200, Warf 10, Methodological Study, International, AGE, rac-3-(alpha-acetonylbenzyl)-4-hydroxycoumarin, Anticoagulant Agent, wide, dInR, Agents, Patient, 4-hydroxy-3-(3-oxo-1-phenylbutyl)-, DILR, Rodafarin, Dir-b, Dir-a, inherited genetic, Apo-Warfarin, HSPABP2, Cytochrome, anticoagulante, Procedures, Cytochrome P450 MP 4, dInsR, Cytochrome P450 MP 8, 2210017D18Rik, dCHIP, P-450 CYP2C9, Cyp4f14, Cigarette, lnR, SCAR16, anticoagulants, broad, narrow, Anticoagulant Drugs, 4-Hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one, Coumadin response, Agent, Indirect Thrombin Inhibitors, DL-3-(alpha-acetonylbenzyl)-4-hydroxycoumarin, dinr, DmelCG5203, IR, DInr, reduced, rac-3-(alpha-phenyl-beta-acetylethyl)-4-hydroxycoumarin, Alcohol Consumption, P450IIC9, Alcohol Intake, Kumadu, Studies, PB-1, tiny, Thrombin Inhibitors, Coumadin, Technique, 4-hydroxy-3-[(1RS)-3-oxo-1-phenylbutyl]-2H-1-benzopyran-2-one, rac-warfarin, Drugs, reactivity, NY-CO-7, VKCFD2, Cytochrome P-450, CYP2C10, Ratio, DIRH, Genotypes, l(3)05545, Study, 18402, drugs, rac-3-(acetonylbenzyl)-4-hydroxycoumarin, Clients, l(3)er10, DmelCG3924, Pale, VKOR, Habit, Zoocoumarin, dIRH, UBOX1, Preparation, dTH1, rac-1-(4'-hydroxy-3'-coumarinyl)-1-phenyl-3-butanone, 0610033N24Rik, constitutitional genetic, PP1131, Potassium, Pharmaceuticals, small, DH65B, response to Coumadin, Products, Cytochrome P450 PB 1, data, Tedicumar, CG10118, Anticoagulant Drug, RnBP, Alcohol Drinking, P450 PB-1, CG5203, GlcNAc 2-epimerase, Medications, Gen-Warfarin, l(2)04405, Intake, Client, CPC9, Consumption, Concept, Warfarin, er10, N-acetyl-D-glucosamine 2-epimerase, International Normalized, Genogroup, Drinking, Indirect, Anticoagulant Agents, chemical analysis, warfarin, racemic warfarin, CYP2C, Sodium, background, techniques, DIRbeta, Coumafene, DTH, CYPIIC9, MST576, Warfarin Potassium, CPF2, Ple, Pharmaceutic Preparations, underdeveloped, Ldb, LDB, INR, Inr, alcohol consumption, INS, Chromatin Immunoprecipitation, Anticoagulation Agents, patient, Cyp4f2, CG3924, Warfarin Sodium, introduction, Alcohol Intakes, Marevan, Drug, Genogroups, Preparations, dLDB/Chip, DL-warfarin, Therapeutic, Cytochrome P450 PB-1, inr, dTH65B, renin-binding protein, assay, response, VII, Pharmaceutical Products, hereditary, CG18402, methodology, Habits, Pharmaceutical Preparation, Indirect Thrombinfalse610K_imputed - samples610k genotyping imputed on Hapmap 3 and 1000G Phase 1 CEU2015-03-09 14:36:08EGAD00010000704960626739746EGAC00001000301EGAS00001001130