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

Pharmacogenomics. 2016 Aug;17(13):1425-39. doi: 10.2217/pgs-2016-0061. Epub 2016 Aug 4.

Abstract

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.

Keywords: CYP2C9; CYP4F2; VKORC1; genome-wide association study; prediction models; time in therapeutic range; warfarin; warfarin dose.

MeSH terms

  • Aged
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Anticoagulants / therapeutic use*
  • Cytochrome P-450 CYP2C9 / genetics
  • Cytochrome P450 Family 4 / genetics
  • Ethnic Groups / genetics
  • Female
  • Genome-Wide Association Study
  • Genomics
  • Genotype
  • Hemorrhage / chemically induced*
  • Hemorrhage / epidemiology
  • Hemorrhage / genetics*
  • Humans
  • International Normalized Ratio
  • Male
  • Polymorphism, Single Nucleotide
  • Precision Medicine
  • Vitamin K Epoxide Reductases / genetics
  • Warfarin / administration & dosage*
  • Warfarin / adverse effects
  • Warfarin / therapeutic use*

Substances

  • Anticoagulants
  • Warfarin
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases