Medical advancement stomps on. This week, Genetics takes front stage.
Really, it’s cool. I know; I was a skeptic too. That is, until I read this most amazing paper on the real-life clinical utility of knowing the whole genome of a person. It felt like peering into the future of medicine.
Background from the real world:
Both patients have “the look” of fitness. Despite their fifty or so birthdays, their faces are lean and chiseled, like those of the high school cross country runner. Underneath the grey hair on their chests are youthful sinewy muscles, devoid of the usual middle age softness. As we talk, they sit upright on the edge of their chair listening for clues to the holy-grail of Cardiology: the prediction and prevention of cardiac events.
One has had a cardiac stent, and the other a sibling who died of sudden death from a heart attack. Since these seminal events, both of these patients have embraced the heart-healthy program. They exercise furiously, eat a Mediterranean diet, take statins, fish oil and CoQ-10. Both could be poster-boys for the AHA program.
“What else can I do,” they each ask? There must be more tests, or more therapy, or more certainty.
But no matter how vigorous the search for answers, certainty in predicting cardiac events is like the asymptote–it gets close, but never intersects. As a pragmatist, and a doctor who sees the forest rather than the trees, I offer that in 2010, there is little else to test for that would convey any more useful clinical relevance. “Keep going as you are, but don’t forget to enjoy the journey along the way. Two or three M+Ms or a light beer once a year is probably ok,” I add with a grin.
Here comes the part where genetics gets us closer to knowing and shaping the future…
As reported comprehensively at CardioBrief (original study published in Lancet), researchers from Stanford and MGH were able to glean real clinical utility from an integrated analysis of a complete human genome. The patient was real. He was an asymptomatic forty year old man with a strong family history of heart disease and sudden death. By looking at millions of his AT-CG pairs the researchers were able to identify strikingly pertinent clinical issues, like predispositions to disease and markers of drug metabolism. Like my two patients, he exercised regularly, and other than osteo-arthritis, he had no manifestations of any ongoing disease. Yet, analysis of his genome revealed: genes that predisposed to coronary artery disease, Type II Diabetes, and some forms of cancer. There were three variants associated with the risk of sudden death, a Lp(a) variant associated with lipid abnormalities and familial coronary artery disease.
In addition to these disease-predicting gene variants, this patient also had highly relevant genetic information on how he would interact with future pharmacologic treatments. His personal genome revealed a possible resistance to clopidogrel (Plavix), an important blood thinner. (Knowing a patient may be resistant to a specific drug might become a highly important issue in the future.) Also, he had DNA that suggested a favorable response–or lack of muscle side effects–from statins. If warfarin was ever needed in the future, his genes suggested he would require a lower than usual dose.
As if all this information wasn’t enough, he even had a gene for arthritis, which ran in his family, and indeed he had a sore knee for years.
These revelations are astounding. Genetic analysis with this kind of clinical specificity will likely change how we diagnosis present conditions, predict future events, and in many cases, may even allow for a-priori adjustment of important pharmacologic therapy.
Is this too much information? As outlined in an accompanying editorial, the ethical permutations are numerous.
“Even if the direct cost of sequencing whole-individual genomes becomes affordable, there are many practical challenges that will need to be overcome if the personal genome is going to enter clinical practice. Arguably of greater importance are ethical issues: who should have their genome sequenced, what counselling should be provided before and after testing and by whom, and who should have access to an individual’s genetic information. Whereas these issues are familiar in genetic testing, the scale of the data contained within each personal genome, and the potential implication for so many different aspects of an individual’s health (and the health of their relatives), mean that these issues will need to be even more carefully considered (and legislated on where necessary) to prevent misuse.”
What about the cost of counseling a patient on each of these 100 or so gene variants? Many patients with AF already worry too much. We can now add to that spreadsheet log of AF episodes, a 100-point list of clinically relevant gene variants. Ouch.
Although widespread application of this whole genome sequencing is futuristic, just this past month I sent a patient for genetic testing. The patient was very young, had a strong family history of sudden death, and had significant abnormalities on the ECG. Genetic analysis revealed a novel mutation in an important cardiac K+ channel. Sure, a decision to recommend lifelong therapy with an implanted ICD could have been made without the genetic analysis, but having DNA evidence of disease is reassuring to both the patient and doctor.
Knowledge is good, but dealing with the complexities of knowing our DNA is going to get complicated.
To quote a famous retired basketball player, “I may be wrong, but I doubt it,” I predict we will be hearing much more about this important study in the years to come.