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

• Main 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
• Other Authors: Xiamen Chang Gung Hospital
• Format: Article
• Published: 2020
• Subjects: Immunology and Microbiology; Medicine
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/60001
• Institution: Mahidol University

© 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.