Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians

Wang CW 1 , Tassaneeyakul W 2 , Chen CB 3 , Chen WT 4 , Teng YC 5 , Huang CY 6 Show all authors , Sukasem C 7 , Lu CW 8 , Lee YS 9 , Choon SE 10 , Nakkam N 2 , Hui RC 5 , Huang YH 11 , Chang YC 12 , Lin YY 13 , Chang CJ 14 , Chiu TM 15 , Chantratita W 16 , Konyoung P 17 , Lee CN 18 , Klaewsongkram J 19 , Rerkpattanapipat T 20 , Amornpinyo W 21 , Saksit N 2 , Rerknimitr P 22 , Huang YH 12 , Lin SH 23 , Hsu CK 24 , Chan CC 25 , Lin YJ 14 , Hung SI 26 , Chung WH 27 , Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium

Affiliations 

  • 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
J Allergy Clin Immunol, 2021 04;147(4):1402-1412.
PMID: 32791162 DOI: 10.1016/j.jaci.2020.08.003

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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