Genetically Tailored Therapy

I recently heard an ad for Vanderbilt University on a national radio program.  The ten-second spot was marketing a new feature available only at their medical center: “This program brought to you by Vanderbilt Medical Center, where doctors use genetic testing to tailor your treatment of cholesterol” (or something like that—as you age your memory starts to fade a bit).  Immediately my imagination was off to the races, envisioning what a consult with one of their doctors must be like.

Good afternoon, Mr. Smith.  Welcome to our clinic.  Before we get into treating your cholesterol, let’s take a moment to review the volumes of genetic information we’ve gleaned from the drop of blood you provided.

It appears from your genetic profile that you have several genes predisposing you—or perhaps even condemning you—to an eventual death from heart disease.  It's lucky you wasted no time seeking our expertise here at Vanderbilt.

To start off, you appear to have the RiP variant of the CR0K_e1 gene at the tail end of your number 13 chromosome.  This, of course, is the one that triggers a massive coronary as you're blowing out the candles on your 53rd birthday.  Normally, your average doctor—one not armed with the latest genetic technology—would simply put you on something like Crestor, but we know from your profile that such an approach would only get you through to next year’s snow-shoveling season.

With our unique battery of tests, we can do better.

You are homozygous for the Cm_PLNS-sux gene, which programs for poor adherence to doctors' advice, thereby limiting the choice of twice daily drugs such as generic niacin.  Fortunately, this predisposition is offset by your NaG₁ gene, which leads you to marry someone who will hover over you day and night and scold you if you miss a single dose.  Your SuKT-1n gene has extensive penetrance and leads you to believe every daytime TV ad you see about erectile dysfunction—leading us to choose an expensive branded statin—but your NK_L-Dim gene makes you such a penny pincher you'll only allow us to prescribe the cheapest generic.

Our medical team debated your case and came to the conclusion, based on your co-dominant trait for complaining endlessly about every ache and pain, that we'd actually rather not take you on as a patient and will be dismissing you immediately.  At first our legal team warned us against cutting you loose, fearing that your autosomal recessive LtG⁸ gene would lead you to hire a high-profile lawyer to sue us, but once we realized you are strongly positive for the Alz4 gene (dementia starting at age 40) we all had a good laugh and breathed easier.

So, Mr. Smith, we wish you well.  Don't lose sleep about the whole "dead at 53" thing—you'll forget all that as soon as you're out the door.

Forgive my descent into absurd mockery for cheap laughs at the expense of what I’m sure is a highly esteemed medical center.  The truth about Vanderbilt’s offer of tailored drug therapy is that they are indeed taking advantage of a known genetic abnormality that predisposes a small portion of the population to suffer untoward effects from our most frequently prescribed statin medications.   The panel of genetic tests they offer has the ability to detect patients who have the variant SLCO1B1 gene that regulates how the liver deals with most statin medications. Individuals possessing this trait are apparently twenty times more likely to have muscle inflammation and breakdown when placed on high doses of medications such as simvastatin (Zocor).

The service they offer is actually part of a research study looking at the SLCO1B1 and 33 other genes that can theoretically impact a patient's response to various medications.  So far, according to the Vanderbilt website, the only "tailoring" consists of a clinician receiving an alert from their database "before being able to prescribe simvastatin if a patient is at increased risk for developing clinically meaningful side effects."

This may not seem like much (especially when compared to the audacity of their ad) but it is, I assure you, the start of something big.  We never put too much thought to it, but there are many very common drugs that affect people differently depending on their underlying genetic make-up.  A few years ago when Plavix (clopidogrel, an anti-clotting drug commonly used to prevent coronary stents from failing) first came on the market, we saw that a small portion of the population derived little or no benefit from its action.  Further investigation unearthed the presence of a genetic variant (CYP2C19) that results in lower effective blood levels of the active drug, and consequently a higher risk of recurrent heart attack.  In March, 2010, the Food and Drug Administration warned that as many as 14% of the population may fall into this class and that genetic testing should be considered.  The Vanderbilt research protocol is already testing for the CYP2C19 variant as well as genes that can affect a patient’s response to other drugs.

Genetic evaluation may also be of use in other areas of cardiac care.  We know that there are 13 heritable conditions that can lead to potentially life-threatening arrhythmias, such as hypertrophic and dilated cardiomyopathies, long QT syndrome, and Brugada syndrome.  The problem with applying such testing to the general population is that these abnormalities are relatively rare (1/500 to 1/10,000 people) and that testing is far from cost-effective.

I suspect that we’ll see more opportunities in the future to genetically screen people for suitability to various therapies.  Many common illnesses (such as hypertension, depression, and chronic pain) tend to be multifactorial, with patients responding quite differently to the wide range of available therapeutic options.  Our current approach is to simply try a treatment that we think will work and sit back and see if it helps.  This trial-and-error approach takes time and is often not terribly effective.

In order for genetic tailoring to become truly useful we’d need to know much more about the genetic basis for disease and develop drugs that target those particular mechanisms.  If we get to that point we’ll be able to initiate the most effective drug right from the start and expect immediate results.

From that point it wouldn’t be too much of a stretch to imagine a day when your doctors can provide you the service I imagined in the opening paragraphs.

And if you believe that, you’re probably strongly positive for the G_uL-1bL gene.