Nontaya Nakkam1, Parinya Konyoung2, Warayuwadee Amornpinyo3, Niwat Saksit4, Somsak Tiamkao5, Usanee Khunarkornsiri2, Kanyarat Khaeso1, Oranuch Pattanacheewapull6, Teekayu Plangkoon Jorns7, Pansu Chumworathayi8, Wichittra Tassaneeyakul1. 1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 2. Pharmacy Unit, Udon Thani Hospital, Udon Thani, Thailand. 3. Division of Dermatology, Department of Internal Medicine, Khon Kaen Hospital, Khon Kaen, Thailand. 4. Unit of Excellence on Pharmacogenomic Pharmacokinetic and Pharmacotherapeutic Researches (UPPER), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand. 5. Integrated Epilepsy Research Group; Division of Neurology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 6. Pharmacy Department, Khon Kaen Hospital, Khon Kaen, Thailand. 7. Orofacial Pain Unit, Department of Oral Biomedical Sciences, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand. 8. Pharmacy Unit, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Abstract
AIMS: Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients. METHODS: Ninety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined. RESULTS: Only 2 HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% confidence interval = 20.24-97.09, corrected P-value = 6.80 × 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an odds ratio of 81.00 (95% confidence interval = 32.39-202.56, corrected P-value = 3.84 × 10-34 ). There is no association between EPHX1 c.337 T > C polymorphism and all phenotypes of CBZ-induced SCARs. CONCLUSION: The HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.
AIMS: Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients. METHODS: Ninety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined. RESULTS: Only 2 HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% confidence interval = 20.24-97.09, corrected P-value = 6.80 × 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an odds ratio of 81.00 (95% confidence interval = 32.39-202.56, corrected P-value = 3.84 × 10-34 ). There is no association between EPHX1 c.337 T > C polymorphism and all phenotypes of CBZ-induced SCARs. CONCLUSION: The HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.
Keywords:
EPHX1; HLA-A*24:07; HLA-B*15:02; Stevens-Johnson syndrome; carbamazepine; drug reactions with eosinophilia and systemic symptoms; epoxide hydrolase; severe cutaneous adverse drug reactions; toxic epidermal necrolysis