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=14

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=<p><bold>Introduction:</bold> 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 (<italic>HLA</italic>) polymorphisms play important roles in the development of drug-related SCARs. This study aimed to extensively characterize the associations between <italic>HLA</italic> genetic polymorphisms and several phenotypes of SCARs related to beta-lactam antibiotics.</p><p><bold>Methods:</bold> 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 the control group. Genotyping of <italic>HLA</italic> class I and class II alleles was performed.</p><p><bold>Results:</bold> Six <italic>HLA</italic> alleles including <italic>HLA-A*01:01</italic>, <italic>HLA-B*50:01</italic>, <italic>HLA-C*06:02</italic>, <italic>HLA-DRB1*15:01</italic>, <italic>HLA-DQA1*03:01</italic>, and <italic>HLA-DQB1*03:02</italic>, were significantly associated with beta-lactam antibiotics-related SCARs. The highest risk of SCARs was observed in patients with the <italic>HLA-B*50:01</italic> allele (OR = 12.6, 95% CI = 1.1–142.9, <italic>p</italic> = 0.042), followed by the <italic>HLA-DQB1*03:02</italic> allele (OR = 5.8, 95% CI = 1.5–22.0, <italic>p</italic> = 0.012) and the <italic>HLA-C*06:02</italic> allele (OR = 5.7, 95% CI = 1.6–19.9, <italic>p</italic> = 0.011). According to the phenotypes of SCARs related to beta-lactam antibiotics, the higher risk of SJS/TEN was observed in patients with <italic>HLA-A*03:02</italic>, <italic>HLA-B*46:02</italic> (OR = 17.5, 95% CI = 1.5–201.6, <italic>p</italic> = 0.033), <italic>HLA-A*02:06</italic>, <italic>HLA-B*57:01</italic> (OR = 9.5, 95% CI = 1.3–71.5, <italic>p</italic> = 0.028), <italic>HLA-DQB1*03:02</italic> (OR = 7.5, 95% CI = 1.8–30.9, <italic>p</italic> = 0.008), or <italic>HLA-C*06:02</italic> (OR = 4.9, 95% CI = 1.1–21.4, <italic>p</italic> = 0.008). While eight <italic>HLA</italic> alleles including <italic>HLA-A*02:05</italic>, <italic>HLA-A*02:11</italic>, <italic>HLA-B*37:01</italic>, <italic>HLA-B*38:01</italic>, <italic>HLA-B*50:01</italic>, <italic>HLA-C*06:02</italic>, <italic>HLA-C*03:09</italic>, and <italic>HLA-DRB1*15:01</italic> were associated with AGEP, the highest risk of AGEP was observed in patients with the <italic>HLA-B*50:01</italic> allele (OR = 60.7, 95% CI = 4.8–765.00, <italic>p</italic> = 0.005). Among the four <italic>HLA</italic> alleles associated with DRESS including <italic>HLA-C*04:06</italic>, <italic>HLA-DRB1*04:05</italic>, <italic>HLA-DRB1*11:01</italic>, and <italic>HLA-DQB1*04:01</italic>, the <italic>HLA-C*04:06</italic> allele had the highest risk of beta-lactam antibiotics-related DRESS (OR = 60.0, 95% CI = 3.0–1202.1, <italic>p</italic> = 0.043). However, these associations did not achieve statistical significance after Bonferroni’s correction. Apart from the <italic>HLA</italic> risk alleles, the <italic>HLA-A*02:07</italic> allele appeared to be a protective factor against beta-lactam antibiotic-related SCARs (OR = 0.1, 95% CI = 0.0–0.5, <italic>p</italic> = 3.7 × 10<sup>−4</sup>, Pc = 0.012).</p><p><bold>Conclusion:</bold> This study demonstrated the candidate <italic>HLA</italic> alleles that are significantly associated with several phenotypes of beta-lactam antibiotics-related SCARs. However, whether the <italic>HLA</italic> 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.</p>