A newly identified genetic marker may significantly improve the ability to predict life-threatening reactions to the gout medication allopurinol in U.S. patients.
While the gene HLA-B*58:01 has long been used to screen patients in Southeast Asia — where it accounts for nearly all cases of severe cutaneous adverse reactions (SCARs) — it misses more than one-third of patients at risk in the U.S. and up to 45% of Black individuals who would be at risk of severe reactions if prescribed.
Now, researchers at Vanderbilt University Medical Center have discovered a second gene, HLA-A*34:02, which when tested alongside HLA-B*58:01, could explain risk in over 80% of U.S. patients, according to a study published in JAMA Dermatology.
"We found a new genetic association, HLA-A*34:02, which appears very important as a risk factor in U.S. allopurinol severe cutaneous adverse reactions patients," said lead author Elizabeth Phillips, MD, the John A. Oates Professor of Clinical Research and professor of Medicine, Dermatology, Pharmacology and Pathology, Microbiology and Immunology at VUMC.
"The combination of HLA-A*34:02 and HLA-B*58:01 would help explain risk in over 80% of patients."
Allopurinol is widely prescribed to treat gout, a painful form of arthritis that affects an estimated 6.1 million men and 2.2 million women in the U.S. While SCARs to the drug are rare, they can be life-threatening. The SCAR most strongly linked to allopurinol and HLA gene risk alleles are Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), with respective mortality rates for allopurinol of 20-30% and approximately 9%. Mortality is highest among patients with renal or cardiovascular disease in whom allopurinol use is more common.
"We are more comprehensively identifying that risk for drug reactions can be population specific based on genes prevalent in specific populations," Phillips said.
"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. We are learning that, in populations like the United States that are highly admixed for race and ethnicity, studies need to be conducted to identify the specific risk genes that are relevant."
The study examined 16 patients with confirmed SCARs due to allopurinol, primarily seen at VUMC. Researchers reproduced a strong association with HLA-B*58:01 but found it absent in a significant portion of cases, especially among Black patients, where it was missing in nearly half.
Because the carriage rate of HLA-B*58:01 is roughly five times higher in U.S. Black individuals than in U.S. white individuals, it has been widely assumed to be the predominant genetic risk factor for allopurinol-induced SCAR. This assumption underlies the American College of Rheumatology's conditional recommendation published in 2020 to perform HLA-B*58:01 screening before prescribing allopurinol to U.S. Asian and Black patients.
However, the study demonstrates that important gaps remain, indicating that HLA-B*58:01 alone does not fully explain risk and that caution is warranted when counseling all populations about the risk of allopurinol-induced SCAR.
"Ultimately we would 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 said.
