Just the thing to scratch that itch

Genetic link to drug-induced skin reaction may help determine who gets which meds

By Brian Hoyle

For some people, a simple prescription of corticosteroids, non-steroidal anti-inflammatory agents, or seizure-controlling drugs like carbamazepine may be hazardous. Stevens-Johnson syndrome, the severe, even life threatening, skin reaction to drugs like these, is relatively infrequent in Caucasians, but crops up four to five times as often in Han Chinese, with 8% suffering from the syndrome. However, a newly discovered genetic link to the syndrome may mean help is at hand for affected Chinese-Canadians.

Dr Yuan-Tsong Chen of Duke University in North Carolina and the Academia Sinica in Taipei, Taiwan reported in the April 1 issue of Nature that a mutation in or near an immunologically-important gene has a "striking association" with carbamazepine-induced Stevens-Johnson syndrome in Han Chinese people.

Dr Chen's group figured this out by comparing different genetic regions between 44 patients with carbamazepine-induced syndrome, 101 carbamazepine-tolerant patients who had uneventfully taken the drug for at least three months, and 93 people from the general population.

The researchers reasoned that the skin problem might be caused by mutations in critical genes that either caused a build up of drugs like carbamazepine or kick-started a hyper-response to them. The genetic regions studied were those for cytochrome-P450 enzymes that are involved in drug metabolism, and human leukocyte antigens (HLAs), which are crucial to immune responses involving white blood cells.

Both controls and affected people showed a similar degree of genetic change in the cytochrome-P450 genes, ruling them out as the culprit. But mutations in genes coding for HLAs were more common in people with Stevens-Johnson syndrome than in control groups. In particular, an abnormal version of an HLA gene designated HLA-B*1502 was present in all those with the syndrome, but in only 3% of carbamazepine-tolerant people and 8.6% of the general population.

Moreover, using the drug-tolerant group as a control, the researchers found that if the mutation was present, odds were high that Stevens-Johnson syndrome was too. But if the mutation was absent, the syndrome was absent as well. When the researchers looked at the presence of four HLA mutations (including B*1502) that sit very close to one another, they found this altered quartet in almost 70% of those with the syndrome, but in less than 5% of normal subjects and none of the drug-tolerant patients. This means that, as Dr Chen notes, this association is "the strongest so far described between an HLA marker and a disease."

The connection between the syndrome and B*1502 may help doctors know which patients shouldn't receive carbamazepine. "In the near future, physicians will be able to test patient's genetic makeup before prescribing medications in order to predict those that are likely to have a severe adverse reaction," says Dr Chen in a Duke University press release. "The technology is here and there will be more advances to come."

For the 1.2 billion Chinese worldwide who could benefit from a B*1502-based test to detect the syndrome, this is very good news, though the significance of the finding for other racial groups is not yet known.