HLA‐B*51:01 and CYP2C9*3 Are Risk Factors for Phenytoin‐Induced Eruption in the Japanese Population: Analysis of Data From the Biobank Japan Project

Abstract

CYP2C9*3 and HLA-B alleles are reportedly associated with phenytoin-induced eruption in some East Asian populations; however, this finding is not readily applicable to the Japanese population. Thus, we aimed to investigate the risk alleles using samples and data from BioBank Japan. A total of 747 patients (24 cases and 723 tolerant controls) were selected for analysis. Case-control association studies were conducted, using CYP2C9*3, CYP2C9*27, CYP2C19*2, CYP2C19*3, and HLA-B allele genotype data. CYP2C9*3 carrier status was significantly associated with phenytoin-induced eruption (P = 0.0022, odds ratio 7.05, 95% confidence interval, 2.44-20.4). HLA-B*51:01 showed the most prominent association (P = 0.010, odds ratio 3.19, 95% confidence interval, 1.37-7.48). Including both of these features improved predictive performance, measured as area under the receiver operating characteristic curve, by 10%. CYP2C9*3 and HLA-B*51:01 allele carrier statuses are significantly associated with phenytoin-induced eruption; thus, checking this carrier status before prescription would decrease the incidence of phenytoin-induced eruption in clinical practice.Adverse drug reactions (ADRs) remain a major concern when prescribing medications. In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) reported 40,964 ADR cases in 2012 with 2,710 associated fatalities. 1 ADR prevention is critical, and identifying more risk factors, including genetic factors, may prevent more of the medication-associated reactions.Unlike disease and trait genomic research, not much has been done in pharmacogenomics (PGx). 2 One of the major reasons is

Pharmacogenetic Testing for Prevention of Severe Cutaneous Adverse Drug Reactions

“…The combined assessment of the risk of HLA and CYP2C9 alleles is useful for predicting PHT-induced SCAR in selected Asian populations ( Cheung et al., 2013 ; Chang et al., 2017 ; Su et al., 2019 ). A recent study from Japanese research groups showed that a combination of CYP2C9*3 and HLA‐B*51:01 was associated with PHT-induced hypersensitivity reactions in Japanese population ( Hikino et al., 2019 ). Previously, other study indicated other metabolizing enzyme, CYP2B6, genetic variant involved in nevirapine-induced SJS/TEN.…”

Associations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin‐Induced Cutaneous Adverse Drug Reactions

“…11,20 Recent evidence suggests that the CYP2C9*3 variant may also be associated with increased risk for cutaneous adverse drug events independently of HLA-B genotype. 9,10,[21][22][23] These studies were conducted primarily in Asian populations where the CYP2C9*2 variant is absent and the HLA-B*15:02 allele is common. Therefore, we sought first to determine the association of both CYP2C9*2 and CYP2C9*3 with phenytoin-induced cutaneous adverse events in a large, multi-ethnic cohort where genotype was unknown throughout treatment.…”