Elsevier

Clinica Chimica Acta

Volume 424, 23 September 2013, Pages 73-75
Clinica Chimica Acta

First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele

https://doi.org/10.1016/j.cca.2013.05.008Get rights and content

Abstract

Background

Warfarin is the most frequently prescribed anticoagulant in North America and Europe. It is administered as a racemate, but S-warfarin is principally responsible for its anticoagulant activity. Cytochrome P450 (CYP) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin. Numerous variant alleles of CYP2C9 have been identified. The CYP2C9*12 (rs9332239) allele harbors a P489S substitution in CYP2C9 which has been shown to result in a 40% decline in catalytic activity in vitro.

Cases

Four Caucasian patients with a low mean weekly warfarin dose (MWWD) were genotyped for CYP2C9, VKORC1 and APOE variant alleles. None of the four patients carried the common CYP2C9 variant alleles (*2, *3, *5, *6, *7, *8, *9, *11, *13) despite a relatively low MWWD (23.4 ± 7.94 mg) compared to 208 patients carrying the CYP29C9*1 genotype (32.2 ± 12.65 mg). Given that CYP2C9*12 confers decreased in vitro activity to the enzyme, we investigated whether these patients carried this allele. All four patients were CYP2C9*12 CT heterozygotes. Individual comparisons with patients possessing the same VKORC1 and APOE genotypes also demonstrated lower dose requirements in the patients that possessed CYP2C9*12 allele.

Conclusions

There are no reports of the clinical impact of rs9332239 on CYP2C9 substrates. This is the first report of patients with the rare CYP2C9*12 genotype and lower warfarin dose requirements.

Introduction

Warfarin is a commonly prescribed oral anticoagulant for the prevention of thromboembolic events. However, warfarin has a narrow therapeutic index and a large interindividual variability exists with regard to warfarin dose requirements for appropriate anticoagulation. Factors such as age, weight, height, medications and diet have been shown to contribute to the variability in warfarin dosing [1], [2], [3], [4]. Additionally, a significant proportion of this variability in warfarin requirements appears to be genetically based [5].

Warfarin produces its therapeutic effect through the inhibition of Vitamin K epoxide reductase (VKORC1), a product of the VKORC1 gene [6]. A properly functioning VKORC1 enzyme is required for the activation, of vitamin K-dependent clotting factors (II, III, IX and X). Some VKORC1 genetic variants result in decreased levels of activated clotting factors, a higher tendency towards clinically significant bleeding, and a lower warfarin dose to attain a therapeutic INR [7]. Warfarin is primarily metabolized by CYP2C9-dependent hydroxylation [8]. A significant proportion of the population possesses variant alleles of CYP2C9 that result in decreased metabolic activity leading to decreased warfarin clearance and a higher risk for serious bleeding associated with higher plasma levels of S-warfarin [9]. Patients with CYP2C9 gene variants that confer decreased enzymatic activity require a lower warfarin dose to attain a therapeutic international normalized ratio (INR) [9], [10], [11]. The increasing importance of pharmacogenetics on warfarin dosing is evidenced by the inclusion of information regarding warfarin for gene variants in CYP2C9 and VKORC1 on the product label by the United States Food and Drug Administration (USFDA) [12].

In addition to CYP2C9 and VKORC1, several other gene variants have been implicated in impacting therapeutic warfarin dose including apolipoprotein E (APOE) which facilitates the uptake of vitamin K-rich lipoproteins into cells [13], [14], [15], [16]. Three common ApoE variants have been identified (E2, E3, E4) with ApoE2 and ApoE4 alleles conferring the highest and lowest levels of vitamin K, respectively [24], [25]. Consistent with this, ApoE4 carriers have a lower warfarin dose requirement that carriers of the other ApoE common alleles [17], [18], [19], [20], [21].

There have been many studies focused on several common CYP2C9 gene variants and their impact on warfarin therapeutic dose [10]. A novel CYP2C9 polymorphism (rs9332239, c.1465C > T, CYP2C9*12) has been observed in vitro to confer decreased activity to the enzyme to the probe drug substrate, tolbutamide [22]. However, no information is available regarding the impact that this polymorphism has on drug metabolism in vivo. Here, we investigated the frequency of this variant in a Caucasian population of patients and report on its potential influence on warfarin dose requirements.

Section snippets

Clinical cases

Caucasian and African American subjects were recruited from ambulatory care clinics at Winchester Medical Center and the George Washington University. Inclusion criteria were that each subject must be 18 years old or older and currently receiving warfarin. The subjects signed an informed consent and agreed to have either two buccal swabs or an additional 10 ml of blood drawn for genotype analysis at the time of a scheduled appointment for an INR check. Demographic and clinical data were

Discussion

There is a great deal of literature available on the influence of CYP2C9 genetic variability on warfarin therapeutic dose requirements [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. Here we describe the first clinical report highlighting the potential impact of the rare CYP2C9*12 (rs9332239 1465C > T) allele on therapeutic warfarin dose requirements. The rationale for investigating this variant stemmed from an

Acknowledgments

This study was supported by National Collaboration On Aging and the Professional Practice Plan of the Shenandoah University. Due to space limitations, the authors would like to apologize for the valuable studies that were not included in this manuscript.

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