# Association between HLA alleles and adverse drug reactions. Mechanisms involved

## TL;DR

This paper reviews how specific HLA alleles are linked to adverse drug reactions and explores the immune mechanisms behind these associations.

## Contribution

The paper systematically compiles current evidence and mechanisms linking HLA alleles to drug-induced hypersensitivity reactions.

## Key findings

- HLA alleles are strongly associated with delayed-type hypersensitivity and severe cutaneous adverse reactions.
- Three main immunological mechanisms—hapten/pro-hapten, p-i, and altered peptide models—are proposed for HLA-related adverse drug reactions.
- The review categorizes drug groups and their associated HLA alleles, including ethnic variations in these associations.

## Abstract

Adverse drug reactions (ADRs) represent a major public health problem. A significant subset of these reactions, particularly delayed-type hypersensitivity reactions and severe cutaneous adverse reactions (SCARs), show a strong association with specific alleles of the human major histocompatibility complex (HLA). The following review aims to summarize the current evidence on the associations between HLA alleles and ADR, covering both well-established associations and those with emerging evidence. The proposed immunological mechanisms for these adverse reactions are also outlined, including hapten/pro-hapten, pharmacological interaction with immune receptors (p-i) and the altered peptide models.

A systematic literature search was conducted in the PubMed database (MEDLINE) through April 2025, independently by the authors. A consensus was then reached, with a total of 56 articles being used in this review.

A division by groups of drugs is established (antiretrovirals, aromatic antiepileptics, allopurinol, antibiotics and other drugs), indicating for each of them the HLA involved, the proposed mechanism, ethnicity in which the association was described and the degree of association. A table is included to facilitate consultation of key information.

HLA alleles play a critical role in the pathogenesis of numerous ADRs, and further studies are needed to clarify HLA-ADRs associations and the mechanisms involved.