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

Abstract 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.