New Genetic Marker Could Significantly Improve Allopurinol Safety in U.S. Patients
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A newly identified genetic marker promises to dramatically improve the prediction of life-threatening reactions to allopurinol, a common medication used to treat gout, particularly among diverse populations in the United States.
A long-standing genetic test, focused on the HLA-B58:01** gene, has been utilized in Southeast Asia to screen patients for severe cutaneous adverse reactions (SCARs). However, this test proves insufficient for a significant portion of U.S. patients, missing risk in over one-third and up to 45% of Black individuals. This limitation underscores the need for more complete genetic screening.
Researchers at Vanderbilt University Medical Center have now pinpointed a second gene, *HLA-A34:02, that, when used in conjunction with HLA-B58:01 testing, could explain risk factors in over 80% of U.S. patients, according to a study published in JAMA Dermatology.
Allopurinol is widely prescribed to prevent gout flares and kidney stones, but it carries the risk of severe, perhaps fatal skin reactions known as severe cutaneous adverse reactions (SCARs). While severe adverse reactions to the drug are rare, they can be fatal. The most dangerous SCARs linked to allopurinol and specific HLA gene variations are Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). These conditions carry mortality rates of 20-30% and approximately 9% respectively, with the highest risk among patients with pre-existing renal or cardiovascular disease – populations where allopurinol is frequently used.
The Importance of Population-specific Genetic Risk
The research highlights a crucial understanding of how genetic predispositions to drug reactions can vary significantly across different populations. “We are more comprehensively identifying that risk for drug reactions can be population specific based on genes prevalent in specific populations,” Phillips stated. “Risk in any given population is based on how commonly a drug is prescribed and then the carriage rate of specific genes associated with risk for that drug reaction in that specific population.”
The study, which examined 16 patients with confirmed SCARs linked to allopurinol, primarily treated at VUMC, confirmed the association with HLA-B58:01. However, the gene was absent in a considerable number of cases, particularly among Black patients, where it was missing in nearly half.
Previously,the higher prevalence of HLA-B58:01 – roughly five times greater in U.S. Black individuals compared to U.S. white individuals – led to the assumption that it was the primary genetic risk factor for allopurinol-induced SCAR. this assumption informed the American College of Rheumatology’s 2020 conditional recommendation to screen U.S. Asian and Black patients for HLA-B58:01 before prescribing allopurinol.
However, the new findings demonstrate that relying solely on HLA-B58:01 screening leaves significant gaps in risk assessment. The study underscores the need for caution when advising all populations about the potential risks associated with allopurinol.
Future Directions: comprehensive Drug Hypersensitivity Panels
Looking ahead, researchers aim to develop more comprehensive drug hypersensitivity panels capable of identifying patients at risk for severe reactions to a wider range of medications, regardless of their ethnic background. “Ultimately we woudl like to develop drug hypersensitivity panels that could more comprehensively identify patients at risk for severe reactions to drugs regardless of their population of origin,” Phillips concluded.
This research represents a significant step toward personalized medicine, ensuring safer and more effective treatment for patients relying on allopurinol to manage gout.
Source: Vanderbilt University Medical Center
Journal reference: Campbell, C. N., et al. (2025). HLA-B58:01 and Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in the US. JAMA Dermatology*. doi.org/10.1001/jamadermatol.2025.4240
