AUTHOR=Wattanachai Pansakon , Amornpinyo Warayuwadee , Konyoung Parinya , Purimart Danklai , Khunarkornsiri Usanee , Pattanacheewapull Oranuch , Tassaneeyakul Wichittra , Nakkam Nontaya 

TITLE=Association between HLA alleles and beta-lactam antibiotics-related severe cutaneous adverse reactions

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1248386

DOI=10.3389/fphar.2023.1248386

ISSN=1663-9812

ABSTRACT=Introduction: Beta-lactam antibiotics are one of the most common causes of antibiotics-related severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reactions with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). Recent evidence demonstrated that the human leukocyte antigen (HLA) polymorphisms play important roles in the development of drug-related SCARs. This study aimed to extensively characterize the associations between HLA genetic polymorphisms and several phenotypes of SCARs related to beta-lactam antibiotics.
Methods: Thirty-one Thai patients with beta-lactam antibiotics-related SCARs were enrolled in the study. A total of 183 unrelated native Thai subjects without any evidence of drug allergy were recruited as a control group. Genotyping of HLA class I and II alleles was performed. 
Results: Six HLA alleles were significantly associated with beta-lactam antibiotics-related SCARs in which the highest risk of SCARs was observed in patients with the HLA-B*50:01 allele with an OR of 12.6 (95%CI = 1.1-142.9, P = 0.042). According to the phenotypes of SCARs, the highest risk of SJS/TEN was observed in patients with HLA-A*03:02 or HLA-B*46:02 (OR = 17.5, 95%CI = 1.5-201.6, P = 0.033), followed by HLA-A*02:06, HLA-B*57:01, HLA-DQB1*03:02 and HLA-C*06:02. While the highest risk of AGEP was observed in patients with the HLA-B*50:01 allele (OR = 60.7, 95%CI =4.8-765.00, P = 0.005). Among the four HLA alleles associated with DRESS including HLA-C*04:06, HLA-DRB1*04:05, HLA-DRB1*11:01 and HLA-DQB1*04:01, the HLA-C*04:06 allele had the highest risk in beta-lactam antibiotics-related DRESS (OR = 60.0, 95% CI = 3.0-1202.1, P = 0.043). However, these associations did not achieve statistical significance after Bonferroni’s correction. Apart from the HLA risk alleles, the HLA-A*02:07 allele appeared to be a protective factor against beta-lactam antibiotics-related SCARs (OR = 0.1, 95%CI = 0.0-0.5, P = 3.7 x 10-4, Pc = 0.012).
Conclusion: This study demonstrated the candidate HLA alleles that are significantly associated with several phenotypes of beta-lactam antibiotics-related SCARs. Whether the HLA alleles observed in this study can be used as valid genetic markers for SCARs related to beta-lactam antibiotics needs to be further explored in other ethnicities and larger cohort studies.