Chuang Wei WangWichittra TassaneeyakulChun Bing ChenWei Ti ChenYu Chuan TengCheng Yang HuangChonlaphat SukasemChun Wei LuYun Shien LeeSiew Eng ChoonNontaya NakkamRosaline Chung Yee HuiYen Hua HuangYa Ching ChangYang Yu Wei LinChee Jen ChangTsu Man ChiuWasun ChantratitaParinya KonyoungChaw Ning LeeJettanong KlaewsongkramTicha RerkpattanapipatWarayuwadee AmornpinyoNiwat SaksitPawinee RerknimitrYu Huei HuangShang Hung LinChao Kai HsuCheng Chi ChanYu LinShuen Iu HungWen Hung ChungXiamen Chang Gung HospitalChang Gung University College of MedicineNational Cheng Kung University HospitalNational Yang-Ming University TaiwanChang Gung Memorial HospitalUdon Thani Center HospitalChung Yuan Christian UniversityMing Chuan UniversityChulalongkorn UniversityChung Shan Medical UniversityTsinghua UniversityShanghai Jiao Tong UniversityKing Chulalongkorn Memorial Hospital, Faculty of Medicine Chulalongkorn UniversityChanghua Christian Hospital TaiwanChang Gung UniversityMonash University MalaysiaKhon Kaen UniversityFaculty of Medicine, Ramathibodi Hospital, Mahidol UniversityNational Cheng Kung UniversityKhon Kaen Regional HospitalThai Severe Cutaneous Adverse Drug Reaction Research Group2020-11-182020-11-182020-01-01Journal of Allergy and Clinical Immunology. (2020)10976825009167492-s2.0-85092363324https://repository.li.mahidol.ac.th/handle/123456789/60001© 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.Mahidol UniversityImmunology and MicrobiologyMedicineArticleSCOPUS10.1016/j.jaci.2020.08.003