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 - Funding Information:
Supported in part by grants from the Ministry of Science and Technology, Taiwan (MOST 103-2321-B-182-001, 104-2314-B-182A-148-MY3, 104-2325-B-182A-006, MOST 106-2314-B-182A-037-MY3, 108-2320-B-182A-023-MY3, 108-2622-B-182A-003-CC2, 108-2314-B-182A-104-MY3, 108-2320-B-182A-024-MY2, 108-2314-B-182A-006-MY3, and 109-2320-B-182A-008 -MY3), Chang Gung Memorial Hospital (BMRPG-290011, CIRPG3I0021-2, CIRPG3I0041-2, CLRPG2E0051-3, CORPG3F0041-3, OMRPG3E0041-3, CMRPG1F0111-3, CMRPG2H0081, CMRPG3I0381-2, CMRPG2J0221, CIROG2I0011, CORPG3F0061-3, CORPG3J0321-3, and CMRPG3K0561) and grants from the Thailand Center of Excellence for Life Sciences (TC-12/63), the International Research Network-The Thailand Research Fund (IRN60W003), the Royal Golden Jubilee Ph.D. Program (PHD/0153/2559) and Newton Fund – PhD Placements for Scholars.We thank Dr Wen Lang Fan and the Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan, for providing support with the WGS database including the general population controls from Taiwan in this study; the Taiwan biobank of Academia Sinica for support with the 1100 HLA results of the general population from Taiwan; and the laboratory of Wasun Chantratita, PhD, head of the Center of Medical Genomics, Ramathibodi Hospital/Mahidol University, Thailand, for support with the WGS database including the general population controls from Thailand in this study.
Funding Information:
Supported in part by grants from the Ministry of Science and Technology , Taiwan (MOST 103-2321-B-182-001 , 104-2314-B-182A-148-MY3 , 104-2325-B-182A-006 , MOST 106-2314-B-182A-037-MY3 , 108-2320-B-182A-023-MY3 , 108-2622-B-182A-003-CC2 , 108-2314-B-182A-104-MY3 , 108-2320-B-182A-024-MY2 , 108-2314-B-182A-006-MY3 , and 109-2320-B-182A-008 -MY3 ), Chang Gung Memorial Hospital ( BMRPG-290011 , CIRPG3I0021-2 , CIRPG3I0041-2 , CLRPG2E0051-3 , CORPG3F0041-3 , OMRPG3E0041-3 , CMRPG1F0111-3 , CMRPG2H0081 , CMRPG3I0381-2 , CMRPG2J0221 , CIROG2I0011 , CORPG3F0061-3 , CORPG3J0321-3 , and CMRPG3K0561 ) and grants from the Thailand Center of Excellence for Life Sciences ( TC-12/63 ), the International Research Network-The Thailand Research Fund ( IRN60W003 ), the Royal Golden Jubilee Ph.D. Program ( PHD/0153/2559 ) and Newton Fund – PhD Placements for Scholars .
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.
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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 -