Effect ofVKORC1Haplotypes on Transcriptional Regulation and Warfarin Dose

Abstract

backgroundThe management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 ( VKORC1 ) may affect the response to warfarin. methodsWe conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. resultsWe identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a highdose haplotype group (B). The mean (±SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7±0.2 mg per day for A/A, 4.9±0.2 mg per day for A/B, and 6.2±0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. conclusions VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and highdose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level. abstract The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITA DEGLI STUDI DI PADOVA on November 4, 2014. For personal use only. No other uses without permission.

Adaptative evolution of theVkorc1gene inMus musculus domesticusis influenced by the selective pressure of anticoagulant rodenticides

“…This variability being partly due to genetic polymorphisms in the Vkorc1 gene, numerous studies have been performed to detect new Vkorc1 mutations in patients resistant to AVK. These studies allowed to detect in humans 27 mutations in the coding sequence of the Vkorc1 gene (Bodin, Horellou, Flaujac, Loriot, & Samama, 2005; Bodin, Perdu, Diry, Horellou, & Loriot, 2008; D'Andrea et al., 2005; Harrington, Siddiq, Allford, Shearer, & Mumford, 2011; Harrington et al., 2008; Loebstein et al., 2007; Osman, Enström, Arbring, Söderkvist, & Lindahl, 2006; Peoc'h, Pruvot, Gourmel, Dit Sollier, & Drouet, 2009; Rieder et al., 2005; Rishavy, Usubalieva, Hallgren, & Berkner, 2011; Rost et al., 2004; Schmeits et al., 2010; Watzka et al., 2011; Wilms, Touw, Conemans, Veldkamp, & Hermans, 2008). In rats, 15 missense mutations in the Vkorc1 gene of Rattus norvegicus have been described in Europe (Grandemange, Lasseur, Longin‐Sauvageon, Benoit, & Berny, 2010; Haniza et al., 2015; Pelz et al., 2005, 2012; Rost et al., 2004).…”

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…314 Additionally, the HapMap project has validated and provided information on population frequencies of public databank SNPs thus reducing the chances of investigating nonexistent polymorphisms. This approach has already been successfully used for the identification of genes related to warfarin dose-response levels 315 and to drug-induced weight gain. 297 Nevertheless, this strategy still requires genotyping of large number of variants in clinical samples of moderate-large size.…”

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

“…Moreover, SNPs in both the coding and 5' non-coding regions of the gene are associated with warfarin (a.k.a. coumadin) responsiveness in humans [9]. However, the physiological response to anticoagulants can also be affected or modified by other genes, including cytochrome P450 genes in roof rats from Japan [10] and in humans ( cytochrome P450 2C9 ) (e.g.…”

“…However, the physiological response to anticoagulants can also be affected or modified by other genes, including cytochrome P450 genes in roof rats from Japan [10] and in humans ( cytochrome P450 2C9 ) (e.g. [9]). Nevertheless, while other genes might modify physiological tolerance levels and possibly resistance, this phenomenon is currently investigated in rodents mainly with respect to SNPs in the vkorc1 gene [11]).…”