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Candidate HLA genes for prediction of co-trimoxazole-induced severe cutaneous reactions

Kongpan, Thachanana; Mahasirimongkol, Surakamethe; Konyoung, Parinyag; Kanjanawart, Sirimasa; Chumworathayi, Pansub; Wichukchinda, Nuanjune; Kidkeukarun, Runglaki; Preechakul, Suphanlineej; Khunarkornsiri, Usaneeg; Bamrungram, Warawutk; Supharatwattanakun, Butsabanl; Mootsikapun, Piroonc; Kwangsukstid, Supanidah; Denjanta, Sukandam; Vannaprasaht, Sudaa; Rungapiromnan, Watchareef; Suwankesawong, Wimonf; Tassaneeyakul, Wongwiwatd; Tassaneeyakul, Wichittraa

doi: 10.1097/FPC.0000000000000153
ORIGINAL ARTICLES
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Background Co-trimoxazole is a sulfonamide-containing antibiotic that is effective in the treatment of several infections and for prophylaxis of Pneumocystis jiroveci pneumonia. This drug has been reported as a common culprit drug for the Stevens–Johnson syndrome (SJS) and for toxic epidermal necrolysis (TEN). Human leukocyte antigens (HLAs) play a key role in the immunopathogenesis of severe cutaneous reactions induced by several drugs. This study investigated the association between the HLA class I and HLA-DRB1 polymorphisms and co-trimoxazole-induced SJS/TEN in a Thai population.

Methods Forty-three patients with co-trimoxazole-induced SJS/TEN and 91 co-trimoxazole-tolerant patients were enrolled in the study. HLA class I and HLA-DRB1 were genotyped using the reverse sequence-specific oligonucleotide probe method.

Results The frequencies of three alleles of HLA, namely HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01, were significantly higher in the co-trimoxazole-induced SJS/TEN group compared with controls. The risks for co-trimoxazole-induced SJS/TEN in patients with the HLA-B*15:02, HLA-C*06:02, or HLA-C*08:01 allele were about 3–11-fold higher when compared with those who did not carry one of these alleles. Individuals who carried the HLA-B*15:02-C*08:01 haplotype had a 14-fold higher risk for co-trimoxazole-induced SJS/TEN.

Conclusion Evidence of associations between co-trimoxazole-induced SJS/TEN and HLA alleles including HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01 were found in the study population. These findings may suggest that apart from the HLA molecules, other molecules involved in the molecular pathogenesis of these severe cutaneous adverse drug reactions may play an important role in the susceptibility of individuals to SJS/TEN caused by co-trimoxazole.

aDepartment of Pharmacology

bPharmacy Unit

cDepartment of Medicine, Faculty of Medicine

dFaculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen

eMedical Genetics Center, Medical Life Science Institute, Department of Medical Sciences, Ministry of Public Health

fHealth Product Vigilance Center, Food and Drug Administration, Ministry of Public Health, Nonthaburi

gPharmacy Unit

hDepartment of Medicine, Udon Thani Hospital, Udon Thani

iBuddhachinaraj Hospital, Phitsanulok

jLampang Hospital, Lampang

kRayong Hospital, Rayong

lSongkhla Hospital, Songkhla

mChiangraiprachanukroh Hospital, Chiangrai, Thailand

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.pharmacogeneticsandgenomics.com).

Correspondence to Wichittra Tassaneeyakul, PhD, Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand Tel: +66 81 6594623; fax: +66 43 348397; e-mails: wichitt@kku.ac.th, wichittra.tassaneeyakul@gmail.com

Received January 24, 2015

Accepted May 18, 2015

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