DRUG BUST Alan Cassels

It recently came to my attention that some people react badly to prescription drugs. Really?

Perhaps I was having a Homeresque “doh” moment when I found myself tripping over this fact as I examined the burgeoning world of Internet-based home genetic testing. If you haven’t noticed, there are all kinds of helpful services on the Internet where we consumers can go online and buy personalized genetic testing kits to determine our susceptibility to a variety of diseases. These kits, costing from $300 to $500, consist of a cheek swab you take in the privacy of your own home and then send to the company for analysis. Some people use the genetic tests to satisfy their curiosity about their family history; one site boasts that a personalized test of your DNA can “… demonstrate the role your ancestors played in human history.” Oh, yeah.

Using home-based gene tests can help determine maternal or paternal ancestry and no doubt it is very useful for people who need help answering that nagging question, “Gee, why is it I look so much like the mailman?”

The real money for these companies comes from selling tests that can determine the likelihood of your getting certain diseases, based on an assessment of variations in your DNA sequence. These variations, called single nucleotide polymorphisms – SNPs or “snips” – can be analyzed and linked to differences in health or physical appearance.

So, is all of this just a lot of high-tech snake oil and the world of personalized genetics just another high-tech money drain for the worried well? It’s possible that people seeking answers from their genes may be wasting their money and seriously deluding themselves. When the company sends you back your personalized DNA test, there is often very little your SNPs can tell you about any unique medical traits. Nor do they provide much substantive information related to your genetic makeup in terms of how it might increase or decrease your risk of developing some kind of disease in the future.

One of the more popular online genetic testing companies is 23andMe (www.23andme.com). It is at the forefront of fulfilling that insatiable desire of some people to know everything about their past and future health. While you might be tempted to say that such sites are for suckers, tailored for people who have more money than brains, there might eventually be something of value there. While personalized genetic testing is still in its infancy, there are some very helpful potential uses on the horizon. One ray of hope lies in improving the way you take prescription drugs to treat a disease you have right now, rather than determining which diseases you might develop as you age.

Which brings me back to the fact that people can be hurt by drugs, a fact that might be altered by a fishing expedition in your own genetic pool. The point is that people react differently to drugs, sometimes dramatically differently. Wouldn’t it be nice to know that, given your particular genotype, there might be a greater possibility of avoiding an adverse effect related to the drug?

Our genetic makeup, general health, body size and a whole range of other factors combine to determine our vastly different reactions to drugs. Our ability to predict the effects of drugs in any particular individual is pretty weak – a drug that works fine in one person may provoke a massive reaction in another – so we need constant reminding that taking any particular drug is essentially an experiment. The question then becomes can a genetic test help us take the guesswork out of the experiment?

There are three particular drugs where genetic testing might help people use them more appropriately: The anti-clotting drug, clopidogrel, or Plavix, is taken by people who might have had a heart stent and who may be at risk of blood clots. Clotting blood, in itself, is not all that bad and prevents you from bleeding to death even from a small cut. But if your blood clots inside an artery, you could be looking at a heart attack or stroke. Not good.

Plavix inhibits clotting, but not to the same extent in everyone. Some people have genetic variations that reduce the activity of a critical enzyme called CYP2C19 so the drug may not get converted into its active form in your body. Which is to say, if you are taking Plavix to reduce your risk of heart attacks, strokes and death from cardiovascular causes, the drug may not work. For people with a different genetic makeup, a single dose of Plavix may be like getting a triple dose because of a genetic variation that causes the body to process the drug incredibly efficiently. Those people may be much more at risk from bleeding, which is also potentially fatal.

Do people who take Plavix need a genetic test to see whether they have any genetic weirdness that affects how the drug is processed? My sense is before you decide if you need a genetic test to optimize the use of a drug, you should decide if you need the drug in the first place. People take aspirin for the same reason they take Plavix – to prevent a future heart attack or stroke – and in my reading of the literature, such as the 20,000-patient, randomized, double-blind, multinational study CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), Plavix is shown to be only slightly more effective in reducing rates of heart attack or stroke. It is about 0.5 percent more effective than aspirin, effectively helping about one in 200 people. Yet in terms of whether or not the drug helps you live any longer, both drugs score equally and it won’t matter whether you take Plavix or aspirin. At about 20 times the cost, is Plavix more effective than good, old aspirin? Probably not.

Another drug not only widely prescribed, but for which genetic testing may help, is warfarin (Coumadin®); some people’s genes might be linked to a heightened sensitivity to the drug. People who have been deemed at risk for blood clots often take this blood thinner, which was originally developed as rat poison and is still used as such. It is a very tricky drug and doctors know that finding the exact right dose for any patient is difficult. Too little and the drug won’t have any effect while too much could result in uncontrolled bleeding. What is considered ‘too little’ or ‘too much’ varies enormously between people. This matters a great deal because as one of the most widely prescribed drugs in the world, warfarin’s potential complications, related to dose size, are one of the main drug-related reasons people end up being hospitalized.

Because versions of a gene called CYP2C9 can slow down the body’s ability to break down warfarin, it may accumulate in your bloodstream and you may need much less warfarin than the average person. This genetic variation may be found in as many as 20 percent of people with European ancestry, but it is rarely found in people with Asian or African ancestry. Which leads us to another issue: the ideal dosing for warfarin, as with many other drugs, varies by ethnicity.

Some drugs work so well in some people that they become poisoned by too much of the active ingredient. The HIV/AIDS drug abacavir (trade name Ziagen) is used to treat HIV by helping inhibit an enzyme that helps the virus reproduce. About one in 10 people treated with abacavir have a hypersensitive reaction, including developing a fever, rash, respiratory problems, and so on, symptoms that typically disappear after they stop taking the drug. Some health professionals have called for genetic testing to see if an individual harbours a particular immune marker called HLA-B*5701, before they get abacavir. Suffice to say even if you don’t have this marker, you can have other types of adverse reactions.

At the end of the day, do we need to try to find genetic information in order to use drugs more safely? That’s a good question to which I would answer, “Maybe, but not yet.” Why? Because the science isn’t quite there yet. These tests are expensive and the results, while perhaps suggestive, are never conclusive. You may have a gene that indicates you might be hypersensitive to a drug, but it doesn’t automatically mean you will be. A safe and controlled trial may be a better measure of how well you tolerate a drug.

The bottom line worth remembering is that while we humans are very similar, when it comes to taking drugs, we may be very different. As one very trusted pharmacologist reminds me, the key principle is “Start low and go slow.” Constant vigilance to determine when and under which conditions it is appropriate to take a drug – taking the least amount you need to do the job – is always warranted and looking deep within your genes provides few definitive answers.

Right now, there are only a few drugs for which genetic tests exist, but there promises to be many more as scientists continue to collect data on our SNPs, sniffing out ‘genotypes’ that can predict any risk or reward related to taking a prescription drug.

In future, look out for drug companies that start co-marketing their products with genetic tests. They’ll be selling genetic tests, not so much to offer promises of health, but more to offer avoidance of drug-related adverse effects. Even now, genetic testing is beginning to create hope around a future of designer pharmaceutical regimes where the shape and size of your medicine cabinet depends on your personal genetic makeup.

Alan Cassels is a drug policy researcher at UVic and is writing a consumer’s guide to the sale of direct-to-consumer genetic testing.