Some Athletes' Genes Help Outwit Doping Test

[Polomac]

 Some Athletes' Genes Help Outwit Doping Test      
Written by GINA KOLATA   
Thursday, 01 May 2008
The 55 men in a drug doping study in Sweden were normal and healthy. And all agreed, for the sake of science, to be injected with testosterone and then undergo the standard urine test to screen for doping with the hormone

The results were unambiguous: the test worked for most of the men, showing that they had taken the drug. But 17 of the men tested negative. Their urine seemed fine, with no excess testosterone even though the men clearly had taken the drug.

It was, researchers say, a striking demonstration of a genetic discovery. Those 17 men can build muscles with testosterone, they respond normally to the hormone, but they are missing both copies of a gene used to convert the testosterone into a form that dissolves in urine. The result is that they may be able to take testosterone with impunity.

The gene deletion is especially common in Asian men, notes Jenny Jakobsson Schulze, a molecular geneticist at the Karolinska University Hospital in Stockholm. Dr. Schulze is the first author of the testosterone study, published recently in The Journal of Clinical
catlin.jpg

Dr. Don Catlin said he suspected
some athletes took advantage
of a doping loophole.

Dr. Schulze learned from an earlier study that about two-thirds of Asian men are missing both copies of the gene, as are nearly 10 percent of Caucasians. The prevalence in other groups is not known.

Doping researchers said the study raised questions about what to do next.

"It's disturbing," said Dr. Don Catlin, the chief executive of Anti-Doping Research, a nonprofit group in Los Angeles. "Basically, you have a license to cheat."

Should athletes give DNA samples for scientists to analyze as genes like the testosterone-metabolizing one are found to be important? Or would another approach, the so-called athlete's passport, be sufficient? The passport, favored by the World Anti-Doping Agency, is a record of all of an athlete's screening tests and would detect results that vary from the athlete's baseline values - but it would not include gene testing and therefore may not detect those athletes lacking this gene.

But nothing will happen soon, and certainly not in time for the Beijing Olympics in August.

Testosterone and substances that act like it are the most frequently detected drugs in screening tests of athletes. The antidoping agency reported that these drugs have been implicated in 43 percent of its positive doping tests.

Researchers have long known that some men, Asians in particular, seemed to be able to take the drugs without getting caught, although no one had identified the cause of the phenomenon. Without gene testing, there is no way to know whether any athletes have exploited this doping loophole, but Dr. Catlin says he suspects some athletes discovered their invulnerability by accident and took advantage of it.

Men with the gene deletion still metabolize testosterone, Dr. Schulze says. But, she adds, she does not know where the hormone goes. "We have no idea," she said. "That's what we're trying to find out."

The gene in question adds a chemical, glucuronide, to testosterone. That converts it from a substance that dissolves in oil into one that dissolves in water and urine.

The testosterone screening test looks for testosterone and another substance, epitestosterone, that is produced in parallel to testosterone but does not have testosterone's effects. The antidoping agency considers a testosterone to epitestosterone, or T to E, ratio of four or greater a positive test and follows it with a more expensive and definitive test that asks whether the excess testosterone is of human origin or whether it is from plants. The testosterone used in doping usually comes from plants.

When they conceived of their study, Dr. Anders Rane and Dr. Mats Garle, head of the Doping Control Laboratory at the Karolinska University Hospital, applied for and received a grant from the antidoping agency. Then, to test their hypothesis, the Karolinska scientists injected the men with 500 milligrams of testosterone and looked at T to E ratios over the next 15 days as the testosterone was metabolized.

The men with two normal copies of the gene had T to E ratios that soared to 100; those with one copy of the gene had ratios that reached 50; those with no copies had almost no rise in their ratios and 40 percent of them had a ratio that never reached 4.

Dr. Schulze and her colleagues suggest that athletes be tested to see if they have the testosterone-metabolizing gene. Others said the testing of athletes for this and other genes may be coming soon.

"The specter of doing this is out there," says Dr. Alvin Matsumoto, a testosterone expert at the University of Washington in Seattle and the Veterans Affairs Puget Sound Health Care System.

The World Anti-Doping Agency is studying instead the athlete's passport. It hopes to keep track of each athlete's drug tests to see if any results suddenly change compared to before.

"You are in a situation where you monitor the athlete and you can see right away if there are modifications" in test results, said Olivier Rabin, the science director of the agency.

Dr. Rabin is less enthusiastic about genetic testing because, he said, it raises ethical questions.

But in either case, it is not clear what to do if an athlete has a genetic feature that makes doping tests turn out negative when the athlete is using drugs. The testosterone follow-up test is technically complex and expensive, raising questions about whether it is feasible to use it for as many as two-thirds of Asians and 10 percent of Caucasians.

"The analytical facilities and costs required preclude any routine use of this methodology for screening in antidoping testing," Dr. Schulze and her colleagues wrote.

And the newly discovered gene deletion may be just one reason the T to E ratio test may fail in some men.

There may be more than a dozen testosterone-metabolizing enzymes, said Dr. Shalender Bhasin, a testosterone researcher at Boston University School of Medicine, and it may be necessary to examine all of them to see if gene variations affect test results. He added that there may be differences in the way men and women metabolize testosterone, so a separate study on women would be necessary to determine whether the gene deletion affects their testosterone tests the same way.

Still Dr. Catlin said, the work by the Karolinska scientists offers hope for the future, showing that the doping world is entering a new era.

"To me it's inevitable that we are going to learn more and more about how genes are influencing the outcome of tests," he said. "It's here," he added. "We might as well get used to it."