Whole Genome Sequencing Identifies Genetic Variants Associated with Co-trimoxazole Hypersensitivity in Asians

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, Huang Yu Huei, Shang-Hong Lin, Chao-Kai Hsu, Wen-Lang Fan, Cheng-Chi Chan, Yu-Jr Lin, Shuen-Iu Hung, Wen-Hung Chung
Journal of Allergy and Clinical Immunology 2020 August 10

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 reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). 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 multi-country case-control association study including 151 cases of co-trimoxazole-induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. A whole-genome sequencing (WGS) was performed for the patients and population controls from Taiwan and further validated the results from Thailand and Malaysia.

RESULTS: The WGS study (43 cases vs. 507 controls) discovered that SNP rs41554616, 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, NAT2, and CYP2C8). A replication study using HLA genotyping revealed that HLA-B*13:01 was strongly associated with co-trimoxazole-induced SCAR (combined samples: 91 cases vs. 2545 controls, P=7.2×10-21 ; OR=8.7). The strong HLA association was also observed in the cases from Thailand (P=3.2×10-5 ; OR=3.6) and Malaysia (P=0.002; 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 DRESS (P=4.2×10-23 , OR=40.1).

CONCLUSION: This study identified HLA-B*13:01 is an important genetic factor associated with co-trimoxazole-induced SCAR in Asians.

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