Associations of HLA and drug-metabolizing enzyme genes in co-trimoxazole-induced severe cutaneous adverse reactions

• DOI: 10.1016/j.dmpk.2022.100480
• Publication Date: 2022-10-18T17:18:17Z
• Authors: Nontaya Nakkam; Niwat Saksit; Parinya Konyoung; Warayuwadee Amorn...; Usanee Khunarkorn...; Danklai Purimart; Oranuch Pattanach...; Tanaporn Naewla; Pansakon Wattanachai; Kanyarat Khaeso; Pansu Chumworathayi; Wichittra Tassane...
• Keywords: 0301 basic medicine; 03 medical and health sciences; Polymorphism, Genetic; HLA-B Antigens; Stevens-Johnson Syndrome; Trimethoprim, Sulfamethoxazole Drug Combination; Humans; Anticonvulsants; Alleles; 3. Good health

Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B∗13:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66-26.77, P = 2.94 × 10-4, Pc = 0.0126). Moreover, the HLA-C∗08:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18-33.14, P = 8.60 × 10-4, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs.