30 to 50 per cent of East Asians might carry a genetic trait that blocks the body's ability to process nitroglycerin

Carolyn Abraham:

For years, Toronto cardiologist Peter Liu had noticed that the oldest heart drug on the market had little effect on many of his East Asian patients.

He would prescribe nitroglycerin to improve their blood flow and relieve the crushing chest pains that accompany angina attacks. But before long those patients would be back in his office.

"This was so nice of you to give me the pill," they'd say politely. "But it really doesn't work."

Few heart drugs in the world have been prescribed as often as nitroglycerin has. Canadians filled 2.1 million prescriptions last year. Yet new research from China offers startling numbers to bolster Dr. Liu's observations: 30 to 50 per cent of East Asians might carry a genetic trait that blocks the body's ability to process the drug, rendering it useless.

The mechanism is so striking that scientists at Fudan University in Shanghai suggest doctors reconsider prescribing nitroglycerin to East Asians.

"Physicians need to know this," said population geneticist Li Jin, senior author of the report, which appears this month in the Journal of Clinical Investigation. "For East Asian populations, instead of giving them nitroglycerin, they should probably give them something else if they don't want to take any chances."

Tests to detect the genetic trait are not widely available. But Dr. Li Jin noted there might be an indirect way to identify carriers: "This particular mutation also results in blushing after drinking alcohol."

The Fudan discovery has landed the 130-year-old drug in one of modern medicine's new fields -- pharmacogenomics. The science with the multi-syllabic title stems from the idea that drugs could be tailored to a person's gene type to maximize benefits and minimize side effects.

But since designing drugs for the individual remains a distant goal, research into the genetic traits common in particular groups and ethnic populations has become a proxy in the interim. Critics warn, however, that it could be dangerous to apply these findings in the clinic since nearly all mutations can be found in people of various ethnic backgrounds, albeit at lower frequencies.

Still, the U.S. Food and Drug Administration has approved a heart drug for blacks, although the genetic reasoning remains unknown. Testing of a new lung cancer drug showed the treatment tended to benefit women and some Asians. And Dr. Liu noted that a recent HIV vaccine trial that failed in Caucasians helped Asians.

"With a few exceptions, we assume all medicines work the same for all patients with different ethnic or genetic backgrounds . . . but I suspect [the Fudan discovery] is the beginning of a new trend," said Dr. Liu, director of cardiology research at the University of Toronto.

"We always knew that Chinese patients respond often quite differently from our Caucasian patients, and this is the first tangible mechanism identified to explain this."

Dr. Liu, who also runs a cardiology practice at Toronto General Hospital, said East Asians are known to have a unique cardiovascular profile.

They tend to have lower blood pressure than Caucasians, he said, and a class of blood pressure medication known as ACE inhibitors is not only ineffective in some East Asians, but also causes a chronic cough. Angiotensin drugs to treat hypertension and diabetes can also be administered to many Asians at half the dose. One 2005 MRI study found arterial plaques in Asians actually look different than those in Caucasians.

"Our surgeons know as well," Dr. Liu said, "that when they are doing operations, the bleeding risk in Chinese patients is so much higher . . ."

In 2002, the Japanese government mandated that pharmaceutical companies specifically test their drugs in Japanese patients before they would be allowed for sale in Japan. An embassy official who asked not to be named explained that, "In order to confirm the safety to our people, we have to test these drugs in Japanese people, who could have different gene characteristics. . . . There is so much data for new drugs, but it is from Western populations."

In an interview from Shanghai, Dr. Li Jin said that he was first drawn to the nitroglycerin story after hearing from a colleague in the United States that Asians tended to respond poorly to the drug. But there was little to go on at the time -- the workings of nitroglycerin as a heart drug have been one of medicine's great mysteries.

The explosive compound, first used by Alfred Nobel to make dynamite in 1866, was soon found to relieve chest pains of the workers who inhaled its fumes in the factory. It went on to become one of the first manufactured medications in 1876 -- but one Nobel was too nervous to take to treat his own heart condition.

Yet only in the 1980s did researchers pinpoint the mechanism to explain its coronary benefits, earning themselves a Nobel Prize. The body, they found, converts nitroglycerin to nitric oxide, which relaxes and expands the smooth muscles of blood vessels. This improves blood flow and means the heart has to pump less forcefully to keep blood circulating.

Nitroglycerin has since been used in pill form and in a pump spray to provide quick relief, and as a patch worn for continuous improvement to blood flow. But a study last year concluded that taken continuously, nitroglycerin could injure the lining of blood vessels. Figures from IMS Health in Canada show the drug's use is slowly declining. But it still ranks 55th in the top 100 selling drugs. Canadians spent $68-million on it last year.

Yet not until 2002 did researchers discover the key enzyme, ALDH-2, that helps the body convert nitroglycerin into its helpful form of nitric oxide. When Dr. Lin Jin read the landmark report, he immediately believed he had stumbled on the answer.

"We know that the gene [that produces this enzyme] has an unusual expression in Asians, especially East Asians," Dr. Li Jin said. In fact, earlier studies have estimated that 30 to 50 per cent of Asians have a mutated and inactive form of this gene.

"Other populations have a very low frequency of this," he said.

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