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

• Published in: Journal of allergy and clinical immunology Vol. 147; no. 4; pp. 1402 - 1412
• Main Authors: Wang, Chuang-Wei, Tassaneeyakul, Wichittra, Chen, Chun-Bing, Chen, Wei-Ti, Teng, Yu-Chuan, Huang, Cheng-Yang, Sukasem, Chonlaphat, Lu, Chun-Wei, Lee, Yun-Shien, Choon, Siew-Eng, Nakkam, Nontaya, Hui, Rosaline Chung-Yee, Huang, Yen-Hua, Chang, Ya-Ching, Lin, Yang Yu-Wei, Chang, Chee-Jen, Chiu, Tsu-Man, Chantratita, Wasun, Konyoung, Parinya, Lee, Chaw-Ning, Klaewsongkram, Jettanong, Rerkpattanapipat, Ticha, Amornpinyo, Warayuwadee, Saksit, Niwat, Rerknimitr, Pawinee, Huang, Yu Huei, Lin, Shang-Hung, Hsu, Chao-Kai, Chan, Cheng-Chi, Lin, Yu-Jr, Hung, Shuen-Iu, Chung, Wen-Hung
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021; Elsevier Limited
• Subjects: Acetyltransferase; Acquired immune deficiency syndrome; AIDS; Antibiotics; Causality; Co-trimoxazole; Cotrimoxazole; CYP2D6 protein; Cytochrome P450; Eosinophilia; Ethics; Genetic diversity; Genomes; Genotyping; Glutathione transferase; Histocompatibility antigen HLA; HIV; HLA-B∗13:01; Hospitals; Human immunodeficiency virus; Hypersensitivity; Infections; Infectious diseases; Lymphocytes; Mortality; N-Acetyltransferase 2; Patients; Phenotypes; Pneumonia; Population; Principal components analysis; Prophylaxis; severe hypersensitivity reactions; Single-nucleotide polymorphism; Statistical analysis; Stevens-Johnson syndrome; sulfonamide; Sulfonamides; Toxic epidermal necrolysis; Urogenital system; Whole genome sequencing; Thailand; Malaysia; Taiwan; WGS; OR; Co-trimoxazole; whole-genome sequencing; GSTP1; SCAR; HLA-B∗13:01; EEF2; MPO; GCLC; DRESS; SNP; sulfonamide; NAT2; NPV; PPV; IRB; TEN; SJS; severe hypersensitivity reactions; LAT; MICA
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2020.08.003

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. We aimed to investigate the genetic predisposition of co-trimoxazole–induced SCAR. 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. 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). This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole–induced SCAR in Asians.