Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records

Abstract

Summary. Background: Vitamin K epoxide reductase (VKORC1) is the site of inhibition by coumarins. Several reports have shown that mutations in the gene encoding VKORC1 affect the sensitivity of the enzyme for warfarin. Recently, three main haplotypes of VKORC1; *2, *3 and *4 have been observed, that explain most of the genetic variability in warfarin dose among Caucasians. Objectives: We have investigated the main haplotypes of the VKORC1 gene in a Swedish population. Additional objective was to screen the studied population for mutations in the coding region of VKORC1 gene. Patients/methods: Warfarin doses and plasma S-and R-warfarin of 98 patients [with a target International Normalized Ratio (INR) of 2.0-3.0] have been correlated to VKORC1 haplotypes. Controls of 180 healthy individuals have also been haplotyped. Furthermore, a retrospective analysis of case records was performed to find any evidence indicating influence of VKORC1 haplotypes on warfarin response in the first 4 weeks (initiation phase) and the latest 12 months of warfarin treatment. Results and conclusions: Our result shows that VKORC1*2 is the most important haplotype for warfarin dosage. Patients with VKORC1*2 haplotype had more frequent visits than patients with VKORC1*3 or *4 haplotypes, higher coefficient of variation (CV) of prothrombin time-INR and higher percentage of INR values outside the therapeutic interval (i.e. 2.0-3.0) than patients with VKORC1*3 or *4 haplotypes. Also, there was a statistically significant difference in warfarin dose (P < 0.001) and R-warfarin plasma levels (P < 0.01) between VKORC1*2 and VKORC1*3 or 4 haplotypes. Patients with VKORC1*2 haplotype seem to require much lower warfarin doses than other patients.

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).…”

Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

“…Supporting this is a Swedish study showing the association between the maintenance dosage of warfarin and several VKORC1 genetic polymorphisms (1413 A > G, intron 1 136 C > T, intron 2+837 T > C, and exon 343 G > A). 27) Moreover, Yuan, et al, showed that VKORC1 1413 A > G polymorphism may explain why the Chinese require lower maintenance warfarin dosages than Caucasians. 28) Mushiroda, et al proposed the WRI, which allocates a number to particular combinations of CYP2C9 and VKORC1 SNPs.…”

Pharmacogenetics-Based Coumarin Therapy

“…57 The found that patients with VKORC1*2 haplotype (similar to haplotype A, using the nomenclature of Rieder et al 55 ) had lower warfarin doses and lower therapeutic warfarin levels than other patients. Furthermore, these patients also had a higher percentage of INR values outside the therapeutic interval.…”