Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort

Pharmacogenomics J. 2019 Apr;19(2):147-156. doi: 10.1038/s41397-017-0005-1. Epub 2018 Jan 3.

Abstract

Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2.68 × 10-5, P = 5.81 × 10-4, and P = 5.94 × 10-4, respectively). Required doses of warfarin were the highest for homozygotes of the minor allele at the VDR variants (P < 0.0026). Variants in the VDR gene were associated with the variability in response to warfarin, emphasizing the possible clinical relevance of nuclear receptor gene variants on the inter-individual variability in drug metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Anticoagulants / administration & dosage
  • Anticoagulants / adverse effects
  • Anticoagulants / metabolism
  • Blood Coagulation / genetics*
  • CCAAT-Enhancer-Binding Proteins / genetics
  • Cytochrome P-450 CYP2C9 / genetics
  • Dose-Response Relationship, Drug
  • Estrogen Receptor alpha / genetics
  • Female
  • GATA4 Transcription Factor / genetics
  • Genome-Wide Association Study*
  • Genotype
  • Hepatocyte Nuclear Factor 4 / genetics
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Pregnane X Receptor / genetics
  • Quebec / epidemiology
  • Receptors, Calcitriol / genetics*
  • Receptors, Calcitriol / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Glucocorticoid / genetics
  • Retinoid X Receptor alpha / genetics
  • Vitamin K / genetics
  • Vitamin K / metabolism
  • Warfarin / administration & dosage
  • Warfarin / adverse effects
  • Warfarin / metabolism*

Substances

  • Anticoagulants
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Estrogen Receptor alpha
  • GATA4 Transcription Factor
  • GATA4 protein, human
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • NR1I2 protein, human
  • NR3C1 protein, human
  • Pregnane X Receptor
  • RXRA protein, human
  • Receptors, Calcitriol
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Glucocorticoid
  • Retinoid X Receptor alpha
  • VDR protein, human
  • estrogen receptor alpha, human
  • Vitamin K
  • constitutive androstane receptor
  • Warfarin
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9