Study Identifies Genetic Marker Missing from Common Pharmacogenomic Panels

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but severe hypersensitivity reaction that can progress to organ damage and carries a 3% to 10% mortality rate. Lamotrigine, prescribed to an estimated 2.5 million Americans in 2024 for bipolar and seizure disorders, is among the top five global causes of DRESS, yet risk prediction remains inconsistent. Addressing this gap, a new study identifies a previously missing human leukocyte antigen signal that may better flag lamotrigine-related risk.

Vanderbilt Health researchers identified human leukocyte antigen (HLA)-A*32:01 as a genetic marker for lamotrigine-induced DRESS that is not included in commonly ordered pharmacogenomic panels. Current panels typically assess HLA-B*15:02 and HLA-A*31:01 because those variants are validated for carbamazepine reactions, but neither has been validated for lamotrigine-related risk in a U.S. population. Because a rapid PCR assay for HLA-A*32:01 has already been developed for vancomycin-induced DRESS, the marker is described as inexpensive and immediately testable.

The matched case-control study enrolled 29 patients with lamotrigine-induced DRESS prospectively from 2016 to 2025 at Vanderbilt Health and Mass General Brigham, and compared them with 290 lamotrigine-tolerant controls from Vanderbilt’s BioVU biobank matched by age, sex, and self-reported race. HLA-A*32:01 was present in 12 of 29 cases (41.4%) and 12 of 290 controls (4.1%), corresponding to 16.4-fold higher odds and representing the strongest genetic signal yet reported for lamotrigine-induced DRESS in any population. By contrast, HLA-A*31:01 showed no significant difference, and no participant in the cohort carried HLA-B*15:02.

The findings were published Sept. 2, 2026, in JAMA Network Open. Collaborators included Mass General Brigham, the Mayo Clinic, the University of Florida, and Murdoch University. The authors note limitations, including the small cohort, which was 79.3% white, and limited power to detect anything beyond large effects, cautioning that the absence of other associations should not be overinterpreted. Because HLA-A*32:01 was present in fewer than half of cases, the marker is neither necessary nor sufficient, and a negative result does not exclude risk.

The team estimates that roughly 2,400 patients would need testing to prevent one case, similar to estimates for HLA-A*31:01 and carbamazepine-induced DRESS, and notes that lamotrigine is now the second drug linked to DRESS through HLA-A*32:01, with docking simulations suggesting different binding patterns.

“The test being ordered was built for a different drug, yet for lamotrigine a negative result can literally be misinterpreted as a green light, offering reassurance that the evidence simply does not support,” said corresponding author Elizabeth Phillips, MD, Professor of Medicine in the Division of Infectious Diseases and Director of the Center for Drug Safety and Immunology.

“That performance is in the same range as a test already in routine use for carbamazepine, so it’s not a hypothetical standard — it’s the one the field has accepted,” said first author Matthew Krantz, MD, Assistant Professor of Medicine in the Division of Allergy, Pulmonary and Critical Care Medicine.

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