Associations of HLA and drug-metabolizing enzyme genes in co-trimoxazole-induced severe cutaneous adverse reactions |
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| Institution: | 1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;2. Unit of Excellence on Pharmacogenomic Pharmacokinetic and Pharmacotherapeutic Researches (UPPER), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand;3. Pharmacy Unit, Udon Thani Hospital, Udon Thani, Thailand;4. Division of Dermatology, Department of Internal Medicine, Khon Kaen Hospital, Khon Kaen, Thailand;5. Pharmacy Department, Khon Kaen Hospital, Khon Kaen, Thailand;6. Pharmacy Unit, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan;2. Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan;3. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;4. Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan;5. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan;1. Preclinical Research Unit, Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan;2. Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan;1. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan;2. Department of Micro Engineering, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto, 615-8540, Japan;3. Institute for Glyco-core Research (iGCORE), Gifu University, 1-1 Yanagido, Gifu-shi, Gifu, 501-1193, Japan;1. Drug Metabolism and Pharmacokinetics Research Laboratories, Japan;2. Quantitative Clinical Pharmacology Department, Japan;3. Clinical Development Department III, Japan;4. Translational Science Department I, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan;1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand;2. Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Thailand;3. Department of Pediatrics, Khon Kaen Hospital, Khon Kaen, Thailand;4. Department of Pediatrics, Udon Thani Hospital, Udon Thani, Thailand;5. Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan;6. Department of Pediatrics, Faculty of Medicine, Shimane University, Izumo, Japan |
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| Abstract: | Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B113:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66–26.77, P = 2.94 × 10?4, Pc = 0.0126). Moreover, the HLA-C108:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18–33.14, P = 8.60 × 10?4, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs. |
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| Keywords: | Co-trimoxazole Severe cutaneous adverse reactions SCARs SJS/TEN DRESS Drug-metabolizing enzymes |
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