title: Identification of novel variants associated with warfarin stable dosage by use of a two-stage extreme phenotype strategy.
abstract: Essentials Required warfarin doses for mechanical heart valves vary greatly. A two-stage extreme phenotype design was used to identify novel warfarin dose associated mutation. We identified a group of variants significantly associated with extreme warfarin dose. Four novel identified mutations account for 2.2% of warfarin dose discrepancies.
  
  
  
  Background The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events. Objective To use a two-stage extreme phenotype strategy in order to discover novel warfarin dose-associated mutations in heart valve replacement patients. Patients/method A total of 1617 stable-dose patients were enrolled and divided randomly into two cohorts. Stage I patients were genotyped into three groups on the basis of VKORC1-1639G>A and CYP2C9*3 polymorphisms; only patients with the therapeutic dose at the upper or lower 5% of each genotype group were selected as extreme-dose patients for resequencing of the targeted regions. Evaluation of the accuracy of the sequence data and the potential value of the stage I-identified significant mutations were conducted in a validation cohort of 420 subjects. Results A group of mutations were found to be significantly associated with the extreme warfarin dose. The validation work finally identified four novel mutations, i.e. DNMT3A rs2304429 (24.74%), CYP1A1 rs3826041 (47.35%), STX1B rs72800847 (7.01%), and NQO1 rs10517 (36.11%), which independently and significantly contributed to the overall variability in the warfarin dose. After addition of these four mutations, the estimated regression equation was able to account for 56.2% (R2Adj= 0.562) of the overall variability in the warfarin maintenance dose, with a predictive accuracy of 62.4%. Conclusion Our study provides evidence linking genetic variations in STX1B, DNMT3A and CYP1A1 to warfarin maintenance dose. The newly identified mutations together account for 2.2% of warfarin dose discrepancy.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: X
authors.identifier: 0000-0002-7167-8332
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Mathematics and Statistics, Central South University, Changsha, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cardio-Thoracic Surgery, the Second Xiangya Hospital Hospital of Central South University, Changsha, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Cardio-Thoracic Surgery, the Second Xiangya Hospital Hospital of Central South University, Changsha, China.
authors.forename: G
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000328:Adult; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006349:Heart Valve Diseases / Q000188:drug therapy / Q000601:surgery*; D006350:Heart Valve Prosthesis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012044:Regression Analysis; D015203:Reproducibility of Results; D050827:Syntaxin 1 / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: C000717967:DNMT3A protein, human; C000610189:STX1B protein, human; D050827:Syntaxin 1; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: extreme phenotype; individual differences; polymorphism; rheumatic heart disease; warfarin