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Title: Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians
Authors: 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 Lin
Shuen Iu Hung
Wen Hung Chung
Xiamen Chang Gung Hospital
Chang Gung University College of Medicine
National Cheng Kung University Hospital
National Yang-Ming University Taiwan
Chang Gung Memorial Hospital
Udon Thani Center Hospital
Chung Yuan Christian University
Ming Chuan University
Chulalongkorn University
Chung Shan Medical University
Tsinghua University
Shanghai Jiao Tong University
King Chulalongkorn Memorial Hospital, Faculty of Medicine Chulalongkorn University
Changhua Christian Hospital Taiwan
Chang Gung University
Monash University Malaysia
Khon Kaen University
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
National Cheng Kung University
Khon Kaen Regional Hospital
Thai Severe Cutaneous Adverse Drug Reaction Research Group
Keywords: Immunology and Microbiology
Issue Date: 1-Jan-2020
Citation: Journal of Allergy and Clinical Immunology. (2020)
Abstract: © 2020 American Academy of Allergy, Asthma & Immunology 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.
ISSN: 10976825
Appears in Collections:Scopus 2020

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