Chuang-Wei Wang1, Wichittra Tassaneeyakul2, Chun-Bing Chen3, Wei-Ti Chen4, Yu-Chuan Teng5, Cheng-Yang Huang6, Chonlaphat Sukasem7, Chun-Wei Lu8, Yun-Shien Lee9, Siew-Eng Choon10, Nontaya Nakkam2, Rosaline Chung-Yee Hui5, Yen-Hua Huang11, Ya-Ching Chang12, Yang Yu-Wei Lin13, Chee-Jen Chang14, Tsu-Man Chiu15, Wasun Chantratita16, Parinya Konyoung17, Chaw-Ning Lee18, Jettanong Klaewsongkram19, Ticha Rerkpattanapipat20, Warayuwadee Amornpinyo21, Niwat Saksit2, Pawinee Rerknimitr22, Yu Huei Huang12, Shang-Hung Lin23, Chao-Kai Hsu24, Cheng-Chi Chan25, Yu-Jr Lin14, Shuen-Iu Hung26, Wen-Hung Chung27. 1. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Linkou, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China. 2. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 3. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Linkou, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 4. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; College of Medicine, Chang Gung University, Taoyuan, Taiwan. 5. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan. 6. School of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University, Taichung, Taiwan. 7. Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center, Ramathibodi Hospital, Bangkok, Thailand; Thai Severe Cutaneous Adverse Drug Reaction Research Group, Thailand. 8. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 9. Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan. 10. Hospital Sultanah Aminah, Clinical School Johor Bahru, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Selangor, Malaysia. 11. School of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan. 12. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. 13. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan. 14. Research Services Center for Health Information, Chang Gung University, Taoyuan, Taiwan. 15. Department of Dermatology, Changhua Christian Hospital, Changhua, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan City, Taiwan. 16. Center of Medical Genomics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 17. Pharmacy Unit, Udon Thani Hospital, Udon Thani, Thailand. 18. Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 19. Thai Severe Cutaneous Adverse Drug Reaction Research Group, Thailand; Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand; King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. 20. Thai Severe Cutaneous Adverse Drug Reaction Research Group, Thailand; Division of Allergy Immunology and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 21. Division of Dermatology, Department of Internal Medicine, Khon Kaen Hospital, Khon Kaen, Thailand. 22. Thai Severe Cutaneous Adverse Drug Reaction Research Group, Thailand; Division of Dermatology, Department of Medicine, Faculty of Medicine, Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. 23. Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 24. Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan. 25. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan. 26. Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Department and Institute of Pharmacology, School of Medicine, Infection and Immunity Research Center, National Yang-Ming University, Taipei, Taiwan. Electronic address: sihung@cgmh.org.tw. 27. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Linkou, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing; School of Medicine, Shanghai Jiao Tong University, Shanghai. Electronic address: wenhungchung@yahoo.com.
Abstract
BACKGROUND: Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole-induced SCAR remains unclear. OBJECTIVE: We aimed to investigate the genetic predisposition of co-trimoxazole-induced SCAR. METHODS: We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole-induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia. RESULTS: The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole-induced SCAR (P = 8.2 × 10-9; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole-related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole-induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10-21; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10-5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole-induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10-23; OR = 40.1). CONCLUSION: This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole-induced SCAR in Asians.
BACKGROUND:Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole-induced SCAR remains unclear. OBJECTIVE: We aimed to investigate the genetic predisposition of co-trimoxazole-induced SCAR. METHODS: We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole-induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia. RESULTS: The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole-induced SCAR (P = 8.2 × 10-9; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole-related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole-induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10-21; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10-5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole-induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10-23; OR = 40.1). CONCLUSION: This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole-induced SCAR in Asians.