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Immunity Gene Predicts Severe Adverse Drug Reaction

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Duke Health News 919-660-1306

DURHAM, N.C. -- 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.

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