Immunity Gene Predicts Severe Adverse Drug Reaction

In a study of Han Chinese patients, researchers have for the first time directly linked a gene of the immune system to a severe adverse drug reaction called Stevens-Johnson syndrome (SJS), according to a Duke University Medical Center medical geneticist and collaborators in Taiwan.

The sometimes fatal condition is characterized by a blistering rash that can lead to detachment of the skin and inflammation of the gastrointestinal and respiratory lining. More than 100 drugs — including antibiotics, NSAIDS, anticonvulsants and the gout drug allopurinol — are known to cause SJS in rare cases. The frequency with which particular prescriptions spur the devastating reaction varies among people of different ethnic backgrounds.

Their new test for the predisposing gene could be applied almost immediately to determine which of the 1.2 billion Chinese worldwide would be at risk for the reaction to the popular anti-epilepsy drug carbamazepine (trade name Tegretol), said Y-T Chen, M.D., chief of medical genetics at Duke University Medical Center and director of the Institute of Biomedical Sciences at Academia Sinica in Taiwan. The anticonvulsant is the most common cause of SJS among the Chinese population.

The finding highlights the promise of pharmacogenomics for avoiding drugs’ most serious side effects and might also lead to advances in the clinical trial of new drugs, said the researchers.

A single genetic marker predicted with 100 percent accuracy those who could safely take carbamazepine, the team reported in the April 1, 2004, issue of Nature. Individuals with a particular version of the immunity gene who took the drug suffered the devastating reaction in all but 3 percent of the cases.

Whether the gene variant will predict the drug reaction in people of other ethnic backgrounds remains to be tested, said Chen. However, his team expects that other similar genes will be found to underlie the reaction induced by the many other drugs that have been linked to SJS. Such findings would enable drug-specific genetic screening tests to prevent the condition.

“In the near future, physicians will be able to test patients’ genetic makeup before prescribing medications in order to predict those that are likely to have a severe adverse reaction,” Chen said. “The technology is here and there will be more advances to come.”

Understanding such genetic interactions might also prove a boon to new drug development, said Chen, noting that some drugs have been eliminated in the clinical trial phase because they produced SJS symptoms in some participants.

In the United States, the condition, which is fatal in 10 percent of cases, occurs in approximately 500 people per year. The condition is four or five times more common in the Chinese population in comparison to the U.S., said Chen. Many more people worldwide are at risk of SJS should they take particular prescription drugs, he added.

Adverse drug reactions stem from two primary causes. In some cases, drug concentrations build to toxic levels due to a person’s genetic inability to metabolize the medication. In others, elements of the immune system mobilize and attack the drug, thereby producing the symptoms.

The investigators screened genetic factors known to play a role in drug metabolism and the immune response in three groups:

— 44 patients with carbamazepine-induced SJS
— 101 patients that had taken the drug for three months with no adverse reaction
— 93 healthy individuals not taking the drug.

All patients with SJS carried the genetic variant human leukocyte antigen B* 1502 (HLA-B* 1502), while only 3 percent of those tolerant of the drug carried that version of the HLA gene, the team found.

HLA markers — perhaps most familiar for their use in determining suitable matches for bone marrow transplantation — play a critical role in the immune system’s recognition of foreign invaders, whether infectious agents or foreign substances such as medications, explained Chen.

The team has set out to identify other genetic markers linked to severe adverse reactions to other drugs. They also plan to further examine the precise mechanism underlying the connection between HLA-B* 1502 and carbamazepine-induced SJS.

Collaborators include Wen-Hung Chung, M.D., Hong-Shang Hong, M.D., Hsin-Chun Ho, M.D., Mo-Song Hsih, M.D., and Li-Cheng Yang, M.D., all of Chang Gung Memorial Hospital in Taiwan; Jer-Yuarn Wu, Ph.D.; and Shuen-Iu Hung, Ph.D., of Academia Sinica.