Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians
| Autor: | Jettanong Klaewsongkram, Nontaya Nakkam, Chun-Wei Lu, Yu-Huei Huang, Ticha Rerkpattanapipat, Chaw Ning Lee, Rosaline Chung-Yee Hui, Wichittra Tassaneeyakul, Ya Ching Chang, Chun-Bing Chen, Wen-Hung Chung, Pawinee Rerknimitr, Warayuwadee Amornpinyo, Niwat Saksit, Yang Yu Wei Lin, Chao Kai Hsu, Yen-Hua Huang, Parinya Konyoung, Chonlaphat Sukasem, Shang Hung Lin, Yu Chuan Teng, Siew Eng Choon, Cheng Chi Chan, Cheng-Yang Huang, Chuang Wei Wang, Tsu Man Chiu, Yun-Shien Lee, Chee-Jen Chang, Wasun Chantratita, Wei-Ti Chen, Shuen-Iu Hung, Yu Jr Lin |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty CYP2D6 Adolescent Immunology Population Anti-Infective Agents Urinary Taiwan Single-nucleotide polymorphism Polymorphism Single Nucleotide Drug Hypersensitivity Young Adult 03 medical and health sciences 0302 clinical medicine Asian People Internal medicine Trimethoprim Sulfamethoxazole Drug Combination medicine Genetic predisposition Humans Immunology and Allergy SNP Genetic Predisposition to Disease Adverse effect education Aged education.field_of_study Whole Genome Sequencing business.industry Malaysia Odds ratio Middle Aged Thailand medicine.disease Toxic epidermal necrolysis Anti-Bacterial Agents 030104 developmental biology HLA-B Antigens Case-Control Studies 030220 oncology & carcinogenesis Female business |
| Zdroj: | Journal of Allergy and Clinical Immunology. 147:1402-1412 |
| ISSN: | 0091-6749 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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