Genetic and clinical risk factors associated with phenytoin‐induced cutaneous adverse drug reactions in Thai population

Abstract

ObjectiveThis study aimed to describe the genetic and clinical risk factors associated with phenytoin‐induced cutaneous adverse drug reactions (PHT‐induced cADRs) in Thai patients.MethodA retrospective case‐control study was conducted among 88 PHT‐ cADRs (25 SJS/TEN, 37 DRESS/DIHS and 26 MPE) compared to 70 PHT‐tolerant controls during 2008‐2017. Genotyping was performed by Taqman RT‐PCR (EPHX1 337 T > C, EPHX1 416A > G and CYP2C9*3), pyrosequencing (UGT1A1*28, UGT1A1*6) and polymerase chain reaction‐sequence‐specific oligonucleotide probe (HLA‐B). Chi‐squared test and binary logistic regression were used to identify factors associated with PHT‐cADRs.ResultsMultivariate analysis showed that HLA‐B*46:01 was significantly associated with all PHT‐induced cADRs (OR 2.341; 95% CI, 1.078‐5.084; P = .032). Age of ≥60 years showed a significant association with PHT‐induced SJS/TEN (OR 3.600; 95% CI, 1.214‐10.672; P = .021). CYP2C9*3 was almost reaching statistically associated with an increased risk of PHT‐induced SJS/TEN (OR 4.800; 95% CI, 0.960‐23.990; P = .056). While HLA‐B*56:02/04 was found to have a significant association with PHT‐induced DRESS/DIHS (OR 29.312; 95% CI, 1.213‐707.994; P = .038). Moreover, female gender and HLA‐B*40:01 were associated with an increased risk of PHT‐induced MPE at OR 5.734; 95% CI, 0.910‐58.351; P = .042 and OR 3.647; 95% CI, 1.193‐11.147; P = .023, respectively.ConclusionBoth clinical (advanced age, female gender) and genetic factors (HLA‐B*46:01, CYP2C9*3, HLA‐B*56:02/04 and HLA‐B*40:01) contributed to the risk of PHT‐induced cADRs. Further studies with larger sample size may be warranted to confirm these findings and also the influence of EPHX1 gene.

Association of HLA-B*51:01, HLA-B*55:01, CYP2C9*3, and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population

“…In this study, the association between HLA B*40:01 and PHT-mild moderate reactions in particular, MPE, was found to be stronger when compared to normal healthy controls, confirming previous findings (Sukesm et al, 2020) [ 46 ], which confirmed HLA B*40:01 as a risk factor for PHT-induced MPE (OR 3.647; 95% CI, 1.193–11.147; p = 0.023).This allele could be a drug-specific HLA genetic marker for PHT-MPE. However, a study with a larger cohort is needed to confirm this finding.…”

Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

“…In Malaysia, it was not only found to be associated with HLA-B*15:02 but also with HLA-B*15:13 (Chang et al, 2017). In Thai population, HLA-B*15:02, HLA-B*56:02, HLA-B*38:02, and HLA-B*46:01 were observed to be associated with phenytoin-induced SJS/TEN (Locharernkul et al, 2008;Tassaneeyakul et al, 2016;Sukasem et al, 2020b;Manuyakorn et al, 2020). When prescribing phenytoin to patients, CPIC guideline recommended considering the HLA-B*15:02 genotype first, then other variants such as CYP2C9 and HLA-A*31:01 (Karnes et al, 2020).…”

“…The carriers of allelic variants of CYP2B6 T983C were in 4.2-fold higher risk to develop SJS/TEN due to low clearance of nevirapine (Ciccacci et al, 2013). Studies showed the variation in drug clearance enzyme CYP2C9*3 contributed to phenytoin-related SCARs with reduced drug clearance rate (Chung et al, 2014;Tassaneeyakul et al, 2016;Wu et al, 2018;Su et al, 2019;Sukasem et al, 2020b;Fohner et al, 2020), independently of HLA-B*15:02 risk allele. Glutathione-Stransferases (GST), which is a family of metabolic enzyme, plays a crucial role in the drug detoxification and activates some chemicals in a few cases.…”

GenotypingHLAalleles to predict the development of Severe cutaneous adverse drug reactions (SCARs): state-of-the-art

“…CYP2C9 variants have been associated with phenytoin-induced SCARs, and CPIC recommends consideration of at least a 25% reduction in the starting maintenance dose for patients who are CYP2C9 intermediate metabolizers and a 50% reduction for CYP2C9 poor metabolizers [57,58]. CYP2C9*3 allele has been reported as a marker for phenytoin-induced DRESS in Thais [59][60][61][62]. A study by Chung et al showed that CYP2C9*3 was strongly associated with phenytoin-induced SCARs in Taiwan, Japan, and Malaysia [15].…”