Abstracts

Rationale: Phenytoin (PHT) is one of the most cost-effective antiepileptic drugs (AEDs) used for controlling seizures and seizure prophylaxis. However, the occurrence of severe cutaneous adverse drug reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (HSS) may limit the use of PHT. CYP2C9*3 and HLA-B*15:02 have been reported as predictive markers for PHT-induced SCARs and SJS/TEN respectively in Asians. This study aimed to investigate the association of genetic variants with phenotype specific PHT-induced SCARs in Thai patients.Methods: Forty-one patients with PHT-induced SCARs (16 SJS/TEN and 25 DRESS/HSS) and 100 PHT-tolerant control patients who had received PHT for at least 3 months without evidence of adverse drug reactions were enrolled in this study. Variants in HLA-B, CYP2C9 and CYP2C19 genes were genotyped. Common HLA-B alleles, with frequency higher than 5% in SCARs patients and CYP2C9*3, CYP2C19*2 and CYP2C19*3 were selected as the candidate variants. CYP2C9*2 was excluded from analysis because of low allele frequency and absence in the SCARs group. Multiple logistic regression analysis was performed to determine the association of multiple genetic variants with PHT-induced SCARs. The study protocol was approved by the ethics committee of all the hospitals involved.Results: This study found that HLA-B*13:01, B*46:01 and CYP2C9*3 were significantly associated with PHT-induced SCARs (adjusted OR = 3.932, 95% CI =1.414-10.928, p = 0.009; adjusted OR = 3.174, 95% CI = 1.235-8.154, p = 0.016; adjusted OR = 4.020, 95% CI = 1.047-15.441, p = 0.043, respectively). More importantly, specific phenotype analysis showed that PHT-induced DRESS/HSS were associated with HLA-B*13:01 and B*46:01 (adjusted OR = 5.120, 95% CI = 1.532-17.106, p = 0.008; adjusted OR = 4.521, 95% CI = 1.407-14.531, p = 0.011, respectively). Whereas CYP2C9*3 and HLA-B*15:02 increased the risk of PHT-induced SJS/TEN (adjusted OR = 8.105, 95% CI = 1.370-47.967, p =0.021; adjusted OR = 4.095, 95% CI = 1.051-15.960, p = 0.042, respectively).Conclusions: This study is the first to report the association of HLA-B*13:01 and B*46:01 with PHT-induced DRESS/HSS in Thai patients. The association between CYP2C9*3 and HLA-B*15:02 with SJS/TEN supported the previous studies. These findings suggest that HLA-B* markers are phenotype specific and support that both genetic variations in the immune system and drug metabolism pathway are predictive genetic markers that may play a role in pathogenesis of PHT-induced SCARs. Acknowledgements: We would like to thank The 90th anniversary of Chulalongkorn University Fund and Pharmaceutical Science Research Fund for financial support.