HLA-A*32:01 Linked to Lamotrigine DRESS Risk, With Matthew Krantz, MD

New data presented at the 2026 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting in Philadelphia from February 27 – March 2, strengthen evidence that HLA-A*32:01 carriage is strongly associated with lamotrigine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) in a US cohort. In an interview conducted at AAAAI, Matthew Krantz, MD, from Vanderbilt University Medical Center, discussed the clinical implications of the findings.

“This is really kind of a discovery HLA association given that HLA testing of class 1 and 2 alleles isn't done on a routine basis for all patients and integrated into their electronic health record,” Krantz said. “This kind of test may be most helpful at this point for helping assess causality for patients who experience stress where they're receiving multiple medications at the same time.”

Krantz explained that DRESS presents a particular diagnostic challenge because of its delayed onset. Symptoms typically emerge 2 to 8 weeks after a medication is started, a window during which patients are often exposed to multiple new therapies. This latency makes it difficult to confidently identify the true culprit drug and complicates decisions about which agents can be safely restarted.

“We want to precisely have them avoid medications that put them at risk of recurrent reactions,” he continued.

Investigators recognized antibiotics, allopurinol, and anti-seizure drugs are the main culprits of DRESS. The team sought to see whether HLA-A*32:01 could serve as a genetic predictor of lamotrigine-induced DRESS.

Krantz and colleagues conducted a prospectively identified, multi-institutional case-control study including patients from Vanderbilt University Medical Center (VUMC) and Mass General Brigham. The cohort comprised 30 lamotrigine-induced DRESS cases (RegiSCAR ≥4) and 300 matched lamotrigine-tolerant controls drawn from VUMC’s BioVU biobank, matched 10:1 by age, sex, and self-identified race.

The cases were predominantly female (87%) and largely self-identified White (93%), with a median age of 33 years (interquartile range, 25–56). High-resolution HLA class I typing was performed using Illumina MiSeq, supplemented by HLA imputation from genotyping array data (SNP2HLA). Association testing was conducted at the locus, haplotype, and amino acid levels using midasHLA and R software, with Bonferroni correction applied.

At the locus level, HLA-A*32:01 was strongly associated with lamotrigine-induced DRESS (odds ratio [OR], 12.1; 95% CI, 4.9–29.8; Pc < .001). Carriage rates were 40% among cases versus 5.5% among tolerant controls. No haplotypes met Bonferroni-corrected significance.

From a genetic epidemiology standpoint, an OR of approximately 12 represents a substantial effect size. As Krantz noted in the interview, most common-disease genetic associations yield ORs between 1 and 2. The magnitude of association here supports biologic plausibility and positions HLA-A*32:01 as a meaningful risk marker.

At the amino acid level, the investigators identified 2 significant HLA-A positions associated with DRESS: lysine at position 109 (OR, 2.4; 95% CI, 1.5–3.3; Pc < .001) and serine at position 77 (OR, 1.9; 95% CI, 1.0–2.7; Pc < .001). These findings suggest that structural features of the HLA-A molecule may contribute to altered peptide presentation and T-cell activation in lamotrigine hypersensitivity.

Despite the strength of the association, Krantz emphasized that translation into routine pre-prescription screening requires careful consideration of predictive value.

“At this point, what inhibits the ability to really implement HLA testing in the clinic is that while it may have a decent negative predictive value, meaning that if you do not carry the risk allele you're much less likely to develop the disease, it doesn't completely exclude it,” Krantz said, “That’s some work that needs to continue to be done before this can really be translated into the clinic where clinicians are using it for pre-prescription testing.”

Relevant disclosures for Krantz include Silk Road Medical, Inc., Boston Scientific Corporation, and Tactile Systems Technology Inc.

References

Krantz M, Gangula R, Yu A, et al. HLA-A*32:01 carriage is associated with lamotrigine-induced drug reaction with eosinophilia and systemic symptoms in a US cohort. Journal of Allergy and Clinical Immunology. 2026;157(2):AB428. doi:https://doi.org/10.1016/j.jaci.2025.12.953