Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians,Journal of Allergy and Clinical Immunology

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Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians
Journal of Allergy and Clinical Immunology ( IF 14.2 ) Pub Date : 2020-08-10 , DOI: 10.1016/j.jaci.2020.08.003
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, Wen-Hung Chung

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).