Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians.
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Wang Chuang-Wei, Tassaneeyakul Wichittra, Chen Chun-Bing, Chen Wei-Ti, Teng Yu-Chuan, Huang Cheng-Yang, Sukasem Chonlaphat, Lu Chun-Wei, Lee Yun-Shien, Choon Siew-Eng, Nakkam Nontaya, Hui Rosaline Chung-Yee, Huang Yen-Hua, Chang Ya-Ching, Lin Yang Yu-Wei, Chang Chee-Jen, Chiu Tsu-Man, Chantratita Wasun, Konyoung Parinya, Lee Chaw-Ning, Klaewsongkram Jettanong, Rerkpattanapipat Ticha, Amornpinyo Warayuwadee, Saksit Niwat, Rerknimitr Pawinee, Huang Yu Huei, Lin Shang-Hung, Hsu Chao-Kai, Chan Cheng-Chi, Lin Yu-Jr, Hung Shuen-Iu, Chung Wen-Hung, Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium
Аннотация
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.