HLA allele profiling and association in Thai patients with confirmed beta-lactam hypersensitivity: an NGS-based analysis.

Background: Beta-lactams (BLs) are the most common reported antibiotics associated with hypersensitivity reactions (HSRs). However, evidence for human leukocyte antigen (HLA) associations with beta-lactam hypersensitivity reaction (BL-HSR) remains limited and population-specific, particularly in the Thai population. Objectives: This study aims to explore HLA profiles and investigate associations between HLA class I and II alleles and confirmed BL-HSR in Thai adults, across immediate reactions (IR), non-immediate reactions with mild skin eruption (NIR-mild), and severe cutaneous adverse reactions (SCARs), and to contextualize these findings with regional data. Methods: This study was based on a case-conrtol design with exploratory analysis approach. For cases, we enrolled adult patients with confirmed BL-HSR from three Thai tertiary hospitals. IR and NIR-mild cases were confirmed by positive skin testing and/or drug provocation testing, while SCAR cases were clinically confirmed. Their blood samples underwent whole exome sequencing, and HLA typing was performed. For control group, we derived allele frequency data of HLA genes in Thai populations from previous nationwide studies previous nationwide studies and databases. HLA allele associations were assessed by Fisher's exact test with Bonferroni correction. Subgroup analyses were conducted based on reaction types and culprit drugs. Meta-analyses of specific HLA alleles from Thai and Asian BL-HSR studies were carried out using random-effects model. Results: Thirty-seven patients were included (62.16% IR, 21.62% NIR-mild, 16.22% SCARs). Association analyses identified candidate susceptibility signals for BL-HSR including HLA-DQA1*01:04 (odds ratio (OR) 8.79; 95% confidence interval (CI) 2.01-29.87; adjusted p-value 0.029) and HLA-DQA1*05:05 (OR 5.03; 95% CI 1.66-12.74; adjusted p-value 0.029). HLA-DQA1*05:05 showed stronger association in IR (OR 6.96; 95% CI 2.01-19.25; adjusted p-value: 0.018). Penicillin-induced HSR were potentially associated with HLA-C*07:02, and β-lactamase inhibitor with HLA-DQA1*01:04. However, these signals were not robust in subsequent sensitivity analyses. Meta-analyses provided contextual support for previously reported high-risk alleles in BL-induced SCARs. Conclusion: HLA-DQA1*01:04 and HLA-DQA1*05:05 represent candidate susceptibility signals for BL-HSR in Thai adults, with phenotype- and drug-specific patterns, which require independent validation. These findings, given relatively small sample size and use of population-based controls, may suggest basis for future immunogenetic risk stratification with validation in larger, phenotype-specific populations.