title: Exon sequencing and association analysis of EPHX1  genetic variants with maintenance warfarin dose in a  multiethnic Asian population.
abstract: OBJECTIVE
  Warfarin inhibits vitamin K epoxide reductase, of which microsomal epoxide hydrolase is a putative member. Several studies have found signals of association with warfarin maintenance dose in the EPHX1 gene. The aim of this study was to determine the effects of EPHX1 variants on warfarin maintenance dose in a multiethnic Asian population.
  
  
  METHODS
  We sequenced the exons of EPHX1 using PCR and direct sequencing in 279 patients consisting of three major ethnic groups receiving maintenance warfarin with a stable international normalized ratio. The effects of EPHX1 variants were assessed using multiple linear regression.
  
  
  RESULTS
  An association between an intronic SNP rs1877724 and warfarin maintenance dose was found, with homozygous variant carriers requiring approximately 0.5 mg/day lower than wild type and heterozygotes after adjustment for covariates. However, its contribution is small, explaining only an additional 0.8% of the dose variability. Rare variants were pooled but there was no association between their presence and warfarin maintenance dose. However, the presence of noncoding rare SNPs was significantly associated with warfarin maintenance dose.
  
  
  CONCLUSIONS
  Despite a significant finding in rs1877724, which concurs with an earlier study, overall, genetic variants in EPHX1 do not have a clinically significant impact on warfarin dose requirements in our population.
authors.affiliation: Department of Epidemiology and Public Health, National University of Singapore, Singapore.
authors.forename: Sze Ling
authors.initials: SL
authors.lastname: Chan
authors.forename: Anbupalam
authors.initials: A
authors.lastname: Thalamuthu
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Kee Seng
authors.initials: KS
authors.lastname: Chia
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chuah
authors.forename: Andrea
authors.initials: A
authors.lastname: Wong
authors.forename: Soo Chin
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D018890:Chemoprevention; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000235:genetics*; D005091:Exons / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000502:physiology; D005828:Genetics, Population; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017422:Sequence Analysis, DNA; D013923:Thromboembolism / Q000208:ethnology / Q000235:genetics* / Q000517:prevention & control; D014859:Warfarin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human