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

doi:10.1016/j.jaci.2020.08.003

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/23519

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/23519

Title:	Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians
Authors:	Wang, CW;Tassaneeyakul, W;Chen, CB;Chen, WT;Teng, YC;Huang, CY;Sukasem, C;Lu, CW;Lee, YS;Choon, SE;Nakkam, N;Hui, RCY;Huang, YH;Chang, YC;Lin, YYW;Chang, CJ;Chiu, TM;Chantratita, W;Konyoung, P;Lee, CN;Klaewsongkram, J;Rerkpattanapipat, T;Amornpinyo, W;Saksit, N;Rerknimitr, P;Huang, YH;Lin, SH;Hsu, CK;Chan, CC;Lin, YJ;Hung, SI;Chung, WH
Keywords:	Co-trimoxazole;HLA-B*13:01;severe hypersensitivity reactions;sulfonamide;whole-genome sequencing
Date:	2021
Issue Date:	2022-08-05T09:38:35Z (UTC)
Publisher:	MOSBY-ELSEVIER
ISSN:	0091-6749
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 cotrimoxazole-induced SCAR (P = 8.2 x 10(-9); odds ratio [OR] = 7.7). There were weak associations of variants in cotrimoxazole-related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B13:01 was strongly associated with co-trimoxazole-induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 x 10(-21); OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 x 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-B13:01 and co-trimoxazole-induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 x 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.
URI:	http://dx.doi.org/10.1016/j.jaci.2020.08.003 https://www.webofscience.com/wos/woscc/full-record/WOS:000647154500005 https://ir.csmu.edu.tw:8080/handle/310902500/23519
Relation:	JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY ,2021,v147,issue 4, P1402-1412
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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