title: Influence of NR3C1 and VDR polymorphisms on stable warfarin dose in patients with mechanical cardiac valves.
abstract: OBJECTIVE
  The aim of this study was to evaluate the associations between polymorphisms of VKORC1, CYP2C9, CYP4F2, NR3C1 and VDR genes and stable warfarin doses in Korean patients with mechanical heart valves.
  
  
  METHODS
  Seventeen single-nucleotide polymorphisms (SNPs) in 204 patients with stable warfarin dose were analyzed: VKORC1 (rs9934438), CYP2C9 (rs1057910), CYP4F2 (rs2108622), NR3C1 (rs41423247, rs1800445, rs56149945, rs10052957, rs6198, rs33388, rs6196, and rs244465), and VDR (rs1544410, rs11568820, rs731236, rs757343, rs7975232, and rs2228570). Statistical analyses were conducted to evaluate the associations of gene variations with stable warfarin dose. Number needed to genotype was obtained by calculating the percentage of patients whose predicted dose was at least 20% higher or lower than the actual stable dose.
  
  
  RESULTS
  The combined genotypes of rs7975232 and rs2228570 of the VDR gene revealed a significant association with stable warfarin dose, along with VKORC1, CYP2C9, and CYP4F2 polymorphisms. Patients with the genotype combination GT,TT/CT,CC of VDR rs7975232/rs2228570 required significantly higher stable warfarin dose (5.79±2.02mg) than those with the other genotypic combinations (5.19±1.78mg, p=0.034). Multivariate analysis showed that VDR rs7975232/rs2228570 explained 2.0% of the 47.5% variability in overall warfarin dose. Adding VDR SNP combinations to the base model including non-genetic variables (age, sex, and body weight) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 41.
  
  
  CONCLUSIONS
  This study showed that stable warfarin dose is associated with VDR SNPs along with VKORC1, CYP2C9, and CYP4F2 SNPs.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea.
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Jee Eun
authors.initials: JE
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea.
authors.forename: Boram
authors.initials: B
authors.lastname: Yi
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea.
authors.forename: Yoon Jeong
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea.
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Gwan Yung
authors.initials: GY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea; College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
authors.forename: Joo Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, Yonsei University Medical Center, Seoul 03722, Republic of Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Chang
authors.affiliation: College of Pharmacy, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address: hsgwak@ewha.ac.kr.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Gwak
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006350:Heart Valve Prosthesis / Q000639:trends; D006801:Humans; D019934:International Normalized Ratio / Q000639:trends; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D056910:Republic of Korea / Q000453:epidemiology; D014859:Warfarin / Q000008:administration & dosage* / Q000097:blood
chemical_list: D000925:Anticoagulants; C497713:NR3C1 protein, human; D018167:Receptors, Calcitriol; D011965:Receptors, Glucocorticoid; C579457:VDR protein, human; D014859:Warfarin
keywords: Glucocorticoid receptor gene; Number needed to genotype; Single nucleotide polymorphism; Vitamin D receptor gene; Warfarin stable dose