TY - JOUR
T1 - Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians
AU - Taiwan/Asian Severe Cutaneous Adverse Reaction Consortium
AU - Wang, Chuang Wei
AU - Tassaneeyakul, Wichittra
AU - Chen, Chun Bing
AU - Chen, Wei Ti
AU - Teng, Yu Chuan
AU - Huang, Cheng Yang
AU - Sukasem, Chonlaphat
AU - Lu, Chun Wei
AU - Lee, Yun Shien
AU - Choon, Siew Eng
AU - Nakkam, Nontaya
AU - Hui, Rosaline Chung Yee
AU - Huang, Yen Hua
AU - Chang, Ya Ching
AU - Lin, Yang Yu Wei
AU - Chang, Chee Jen
AU - Chiu, Tsu Man
AU - Chantratita, Wasun
AU - Konyoung, Parinya
AU - Lee, Chaw Ning
AU - Klaewsongkram, Jettanong
AU - Rerkpattanapipat, Ticha
AU - Amornpinyo, Warayuwadee
AU - Saksit, Niwat
AU - Rerknimitr, Pawinee
AU - Huang, Yu Huei
AU - Lin, Shang Hung
AU - Hsu, Chao Kai
AU - Chan, Cheng Chi
AU - Lin, Yu Jr
AU - Hung, Shuen Iu
AU - Chung, Wen Hung
N1 - Publisher Copyright:
© 2020 American Academy of Allergy, Asthma & Immunology
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85092363324
UR - https://www.scopus.com/inward/citedby.url?scp=85092363324&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2020.08.003
DO - 10.1016/j.jaci.2020.08.003
M3 - Article
C2 - 32791162
AN - SCOPUS:85092363324
SN - 0091-6749
VL - 147
SP - 1402
EP - 1412
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 4
ER -