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Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens-Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64-6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41-3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79-12.73, p < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50-16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77-9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97-371.98, p < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50-21.16, p < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs., (© 2021. The Author(s).)

Objective: This study aimed to describe the genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions (PHT-induced cADRs) in Thai patients., Method: A 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., Results: Multivariate 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., Conclusion: Both 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., (© 2020 John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to investigate the association of genetic factors including variants in HLA-B and CYP2C genes and non-genetic factors with phenotype-specific phenytoin (PHT)-induced severe cutaneous adverse reactions (SCARs) in Thai patients., Methods: Thirty-six PHT-induced SCAR cases (15 Stevens-Johnson syndrome (SJS) and 21 drug rash with eosinophilia and systemic symptoms (DRESS)/drug hypersensitivity syndrome (DHS)) and 100 PHT-tolerant controls were studied. Variants in HLA-B, CYP2C9, and CYP2C19 genes were genotyped. Fisher's exact test and multiple logistic regression analysis were performed to test the association of genetic and non-genetic factors with specific type of SCARs., Results: Multiple logistic regression models showed that genetic and non-genetic factors associated with PHT-induced SCARs were specified to its phenotype. HLA-B*13:01, HLA-B*56:02/04, CYP2C19*3, and omeprazole co-medication were strong risk factors of DRESS/DHS (adjusted OR = 13.29, p = 0.0001; adjusted OR = 56.23, p = 0.0007; adjusted OR = 6.75, p = 0.0414; and adjusted OR = 9.21, p = 0.0020, respectively). While CYP2C9*3 and having Chinese ancestry were significant risk factors of SJS (adjusted OR = 10.41, p = 0.0042 and adjusted OR = 5.40, p = 0.0097, respectively). Combined genetic and non-genetic risk factors optimized sensitivity and increased specificity for predicting PHT-induced SCARs., Conclusion: This study showed that distinct genetic markers were associated with phenotype-specific PHT-induced SCARs. Non-genetic factor, omeprazole co-medication, was strongly associated with PHT-induced DRESS/DHS in addition to variants in HLA-B and CYP2C genes. Combined markers may be better predictors for PHT-induced SCARs.