Implication of novel CYP2C9*57 (p.Asn204His) variant in coumarin hypersensitivity

Nahar, Risha; Dube, Divya; Parakh, Rajiv; Deb, Roumi; Saxena, Renu; Singh, T.P.; Verma, I. C.

doi:10.1016/j.thromres.2013.03.019

Cited by 8 publications

(6 citation statements)

References 22 publications

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“…Given that the loss of rs9923231/rs9934438 linkage has been described in some patients, the determination of rs9934438 may provide a better dose adjustment in these cases [52]. The novel CYP2C9*57 haplotype, which was detected in one out of 309 oral anticoagulated patients (0.3%), showed VKA hypersensitivity because of a slower warfarin and ACN metabolism, mandating a dose reduction, and it was associated with multiple bleeding episodes and an increased percentage of INRs above 3.0 [56]. The patient with the novel CYP2C9*57 haplotype was also wild type for the most common gene polymorphisms of VKORC1 and CYP2C9, which may have masked his true dose requirement [56].…”

Section: Discussionmentioning

confidence: 99%

“…The novel CYP2C9*57 haplotype, which was detected in one out of 309 oral anticoagulated patients (0.3%), showed VKA hypersensitivity because of a slower warfarin and ACN metabolism, mandating a dose reduction, and it was associated with multiple bleeding episodes and an increased percentage of INRs above 3.0 [56]. The patient with the novel CYP2C9*57 haplotype was also wild type for the most common gene polymorphisms of VKORC1 and CYP2C9, which may have masked his true dose requirement [56]. Other variants associated with ACN dosage variation in a genome-wide study were CYP2C9 (rs4086116) and CYP2C18 (rs1998591, rs12772169, rs1042194) [57], which have recently shown frequencies at least 0.8% in various population samples [58].…”

Section: Discussionmentioning

confidence: 99%

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Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Jiménez-Varo

Cañadas-Garre

Gutiérrez-Pimentel

et al. 2014

Pharmacogenetics and Genomics

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Jiménez-Varo

Cañadas-Garre

Gutiérrez-Pimentel

et al. 2014

Pharmacogenetics and Genomics

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“…They have been identified as the most common defective alleles and have exhibited reduced metabolic activities, both in vitro and in vivo, for the CYP2C9 substrates, such as warfarin. In addition to these two common alleles, other allelic variants, such as CYP2C9*4 (Lee et al, 2007), CYP2C9*5 (Dickmann et al, 2001), CYP2C9*8 (Liu et al, 2012), CYP2C9*11 (Tai et al, 2005), CYP2C9*12 (O'Brien et al, 2013), CYP2C9*14 (Lee et al, 2014), CYP2C9*35 (Ciccacci et al, 2011), CYP2C9*57 (Nahar et al, 2013), and CYP2C9*58 (Luo et al, 2014), were reported to affect warfarin sensitivity. In this study, we present the case of a Chinese warfarin-sensitive patient who requires only one-half of the normal oral warfarin dose.…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C959*

Dai

Wang

et al. 2015

Drug Metab Dispos

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CYP2C9, one of the most important drug-metabolizing enzymes, is responsible for metabolizing approximately 15% of clinically important drugs, including warfarin, diclofenac, and losartan. Similar to other CYP members, human CYP2C9 exhibits marked genetic polymorphisms among individuals of different ethnicities. In this study, a novel missense mutation (1300A>T) was identified in a warfarin-sensitive patient after a genetic screen of three candidate genes related to high variability in response to warfarin doses. This base transversion leads to an Ile-toPhe amino acid substitution at codon 434 within the CYP2C9 protein, and this new variant has been named a novel allele, CYP2C9*59, by the Human CYP Allele Nomenclature Committee (http://www.cypalleles.ki. se/cyp2c9.htm). The exogenous expression of CYP2C9.59 in insect cell microsomes revealed that, despite a similar protein expression level as wild-type CYP2C9, variant CYP2C9.59 exhibited significantly reduced maximal velocity, V max , and/or increased Michaelis constant, K m , values toward three CYP2C9-specific substrates. Our data suggest that the 1300A>T mutation can greatly decrease the enzymatic activity of the CYP2C9 protein both in vitro and in vivo. IntroductionCYP2C9 is the major CYP2C isoform in humans and is responsible for the metabolism of approximately 15% of all clinically important drugs (Samer et al., 2013;Chen et al., 2014). Similar to other CYP members, CYP2C9 is highly polymorphic across various racial and ethnic populations. These genetic polymorphisms have been shown to have clinical importance, leading to great inter-individual variability and serious adverse effects in the efficacies of many therapeutic drugs (Chaudhry et al., 2014). Alleles CYP2C9*2 (containing a R144C substitution) and CYP2C9*3 (containing an I359L substitution) have been well studied among different ethnic populations. They have been identified as the most common defective alleles and have exhibited reduced metabolic activities, both in vitro and in vivo, for the CYP2C9 substrates, such as warfarin. In addition to these two common alleles, other allelic variants, such as CYP2C9*4 ( Lee et al., 2007) Nahar et al., 2013), and CYP2C9*58 (Luo et al., 2014), were reported to affect warfarin sensitivity. In this study, we present the case of a Chinese warfarin-sensitive patient who requires only one-half of the normal oral warfarin dose. Genetic analysis in that patient revealed an absence of the common mutations in CYP2C9 (*2, *3), VKORC1 (rs9923231 and rs7294), and CYP4F2 (rs2108622) that are usually related to warfarin sensitivity. However, a novel missense mutation (1300A.T) was identified in exon 9 of the CYP2C9 gene. The in vitro functional assessment of this newly found CYP2C9 variant revealed that the substitution of an Ile to a Phe at codon 434 significantly reduced the enzymatic activity of this variant toward all of the tested substrates. Materials and MethodsStudy Subject. The study subject was a 47-year-old male Han Chinese patient who has taken warfarin...

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“…Genetic mutations in its coding gene have been found significantly associated with lowered daily warfarin dose requirement and appear to be more susceptible to the adverse effects during initiation of therapy. To date, several CYP2C9 allelic variants, such as *2, *3, *4, *5, *8, *11, *12, *14, *35, *57 and *58 have been reported to be associated with warfarin sensitivity [13,[31][32][33][34][35][36][37][38]. In this study, we detected another novel allelic variant CYP2C9*60 in a warfarin-sensitive Chinese patient.…”

Section: Resultsmentioning

confidence: 66%

Identification and Characterization of a Novel Cyp2C9 Allelic Variant in a Warfarin-Sensitive Patient

Dai

Wang

et al. 2015

Pharmacogenomics

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Implication of novel CYP2C9*57 (p.Asn204His) variant in coumarin hypersensitivity

Cited by 8 publications

References 22 publications

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C959*

Identification and Characterization of a Novel Cyp2C9 Allelic Variant in a Warfarin-Sensitive Patient

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Implication of novel CYP2C9*57 (p.Asn204His) variant in coumarin hypersensitivity

Cited by 8 publications

References 22 publications

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C9*59

Identification and Characterization of a Novel Cyp2C9 Allelic Variant in a Warfarin-Sensitive Patient

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Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C959*