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

Chuang-Wei Wang; Wichittra Tassaneeyakul; Chun-Bing Chen; Wei-Ti Chen; Yu-Chuan Teng; Cheng-Yang Huang; Chonlaphat Sukasem; Chun-Wei Lu; Yun-Shien Lee; Siew-Eng Choon; Nontaya Nakkam; Rosaline Chung-Yee Hui; Yen-Hua Huang; Ya-Ching Chang; Yang Yu-Wei Lin; Chee-Jen Chang; Tsu-Man Chiu; Wasun Chantratita; Parinya Konyoung; Chaw-Ning Lee; Jettanong Klaewsongkram; Ticha Rerkpattanapipat; Warayuwadee Amornpinyo; Niwat Saksit; Pawinee Rerknimitr; Yu Huei Huang; Shang-Hung Lin; Chao-Kai Hsu; Cheng-Chi Chan; Yu-Jr Lin; Shuen-Iu Hung; Wen-Hung Chung; Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium

doi:10.1016/j.jaci.2020.08.003

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

J Allergy Clin Immunol. 2021 Apr;147(4):1402-1412. doi: 10.1016/j.jaci.2020.08.003. Epub 2020 Aug 10.

Authors

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; 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.

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.

Keywords: Co-trimoxazole; HLA-B∗13:01; severe hypersensitivity reactions; sulfonamide; whole-genome sequencing.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Anti-Bacterial Agents / adverse effects*
Anti-Infective Agents, Urinary / adverse effects*
Asian People / genetics*
Case-Control Studies
Drug Hypersensitivity / genetics*
Female
Genetic Predisposition to Disease*
HLA-B Antigens / genetics*
Humans
Malaysia / epidemiology
Male
Middle Aged
Polymorphism, Single Nucleotide
Taiwan / epidemiology
Thailand / epidemiology
Trimethoprim, Sulfamethoxazole Drug Combination / adverse effects*
Whole Genome Sequencing
Young Adult

Substances

Anti-Bacterial Agents
Anti-Infective Agents, Urinary
HLA-B Antigens
Trimethoprim, Sulfamethoxazole Drug Combination