Matthew Krantz, MD, from Vanderbilt University Medical Center

Matthew Krantz, MD

HLA-A*32:01 Carrier Screening Feasibility Before Lamotrigine, With Matthew Krantz, MD

New data linked HLA-A*32:01 carriage to lamotrigine-induced drug reaction with 

eosinophilia and systemic symptoms (DRESS)

2026 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting in Philadelphi

a, Matthew Krantz, MD, from Vanderbilt University Medical Center, addressed how these data should guide management decisions and whether pre-prescription screening is feasible. He said a team led by Elizabeth Phillips, MD, from Vanderbilt, had developed a rapid single allele assay for 32:01 that uses allele-specific primers.

“You don’t get full HLA typing, but you get a binary result of whether an individual is a carrier for a 3201 or not,” Krantz said. “You also don't get information if an individual has 2 copies of a 3201; you would only get…that binary result. It's not a clinically available test, but in research settings where it's been optimized, these tests can be done with a several-hour turnaround. We do think that if these tests were to have evidence of meeting that threshold of a low number needed to test to prevent 1 case, that this is something that could be translated into the clinic.”

In the recently published multi-institutional cohort, HLA-A*32:01 was present in 40% of lamotrigine-induced DRESS cases compared with 5.5% of matched lamotrigine-tolerant controls, corresponding to an odds ratio of 12.1 (95% CI, 4.9–29.8; Bonferroni-corrected 

 < .001). Although this represents a substantial genetic association, DRESS remains rare. Among individuals exposed to high-risk medications for the requisite 2- to 8-week latency period, approximately 1 in 1000 may develop DRESS. At the population level, incidence is estimated at 1 to 3 per 100,000.

Given this low absolute risk, routine pre-prescription high-resolution HLA typing is not currently standard practice. Krantz noted that most patients will not have existing HLA class I data available to guide lamotrigine prescribing. An exception may include patients undergoing bone marrow or solid organ transplantation, where comprehensive HLA typing is already performed.

In situations where HLA-A*32:01 carriage is known, and lamotrigine is strongly indicated, Krantz suggested a risk-mitigation strategy rather than automatic exclusion. Lamotrigine is associated with a spectrum of cutaneous reactions, ranging from mild maculopapular eruptions to severe hypersensitivity. Standard prescribing protocols already emphasize low starting doses with gradual titration to reduce rash risk. In carriers, clinicians could consider even more cautious dose escalation, closer clinical follow-up, and vigilant monitoring for early systemic symptoms such as a rash.

The original cohort included 30 prospectively identified lamotrigine-induced DRESS cases (87% female; 93% self-identified White; median age 33 years [interquartile range, 25–56]) and 300 matched tolerant controls. Krantz acknowledged that the predominantly White, European ancestry composition limits the ability to detect ancestry-specific risk alleles.

“This really requires collaborative networks of academic medical centers identifying and precision phenotyping these individuals, obtaining… genetic data for sequencing, especially for HLA, to be able to generalize these results,” Krantz said. “We're really the first multi-institutional group to kind of show this. The next step would be for replication at other sites.”

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

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

doi:https://doi.org/10.1016/j.jaci.2025.12.953

Krantz M. HLA-A*32:01 Linked to Lamotrigine DRESS Risk, With Matthew Krantz, MD. HCPLive. Published on February 28, 2026. Accessed on February 28, 2026. 

https://www.hcplive.com/view/hla-a-32-01-linked-lamotrigine-dress-risk-matthew-krantz-md

Videos

HLA-A*32:01 carrier screening may identify patients at elevated risk for lamotrigine-induced eosinophilia and systemic symptoms, Krantz says at AAAAI 2026.

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 

 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.”

. 2026;157(2):AB428. doi:https://doi.org/10.1016/j.jaci.2025.12.953

Prospective case-control data presented at AAAI 2026 demonstrate a 12-fold increased odds of DRESS among lamotrigine-treated HLA-A*32:01 carriers.

Matthew Krantz, MD

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