New Review Puts 'Explosion' of CVD Genomics Into Context

November 30, 2011

November 30, 2011 (Bethesda, Maryland) — A new review on the genomics of cardiovascular disease attempts to put a flood of genetic findings over the past five years into some kind of context for physicians [1].

"Since 2006, there has been a huge explosion of discoveries relating specific genes--and variants in genes--to heart attack, stroke, aortic aneurysm, arrhythmias, and risk-factor traits that has really been quite impressive," one of the authors, Dr Christopher J O'Donnell (National Heart Lung and Blood Institute, Bethesda), told heartwire .

But O'Donnell believes there has been too much hype in terms of predicting the clinical implications of these findings and that a slightly more conservative take on the subject is warranted. "Like anything in medicine, the translation of genomics research is a process that is always going to involve more research to get to evidence-based findings."

Nevertheless, says O'Donnell--who has penned the review with coauthor Dr Elizabeth G Nabel (Brigham and Women's Hospital, Boston, MA) in the December 1, 2011 issue of the New England Journal of Medicine--"I can't help but think we are going to have a faster timeline than in the past.

I can envision a time in my lifetime when most or all patients will have a genome sequence as part of their medical portfolio of data.

"I've worked at the Framingham Heart Study, where risk-factor discovery 40 or 50 years ago took decades to be applied in guidelines and clinical trials. But I can envision a time in my lifetime when most or all patients will have a genome sequence as part of their medical portfolio of data," he commented.

Prediction Only a Small Piece of the Overall Genomics Puzzle

O'Donnell explains that one of the reasons he and Nabel wrote the review is because most of the genetic discoveries of the past five years have arisen from genomewide association studies (GWAS), many of which have not even been published in the medical literature. "So the journal readership may not be aware of all the findings."

Consequently, in the piece, he and Nabel provide a glossary of genetic terms for physicians and two tables outlining the most pertinent recent discoveries from GWAS for common CVDs and risk factors.

There is a new encyclopedia of genetic findings for cardiovascular disease, but each of the chapters has to be now written.

However, there have been unrealistic expectations, O'Donnell believes. "We have potentially done ourselves a disservice in pinning too much hope on prediction as one of the major outcomes of all of this."

During the past 18 months "there's been a pendulum against use of the data for risk prediction, which I think is warranted because risk prediction is really only one small piece of the overall portfolio of opportunities from genomics," and there's no evidence, at present, that it has clinical utility, he says.

The truth is that in these GWAS, each association with disease "tends to be fairly small in its impact clinically. There is a new encyclopedia of genetic findings for cardiovascular disease, but each of the chapters has to be now written" by further study of the underlying biology, he observes.

Nearer-Term Implications: Elucidating Pathways and Pharmacogenomics

O'Donnell and Nabel do point out in their article that there are some nearer-term applications of this genomics research, including the provision of insights into new biologic pathways, "often previously unsuspected," that underlie the cause of diseases. This will in turn enable research into potential novel drug targets, they say.

A second important application is pharmacogenomics. "Discoveries that are provided by GWAS have strengthened the evidence for pharmacogenetic interactions in a number of commonly used cardiovascular drugs," they explain, citing variants in CYP2C9 and VKORC1, which may explain up to 40% of the variation in the adjusted dose of warfarin, which has led to the US FDA revising the label on this anticoagulant drug.

And variations in CYP2C19 that are associated with decreased antiplatelet activity and an increased risk of CVD among those taking clopidogrel have promoted an FDA warning and recommendations for dose adjustment of this drug in patients with this variant, they add.

Evidence of other pharmacogenetic interactions that may be clinically important is also accumulating, they point out. For example, variation in the beta1-adrenergic–receptor gene, ADRB1, is associated with altered responsiveness to beta blockade in heart failure, and a variant in SLC01B1 "has been implicated in statin-related myopathy."

Next Steps: Deep DNA Sequencing Should Yield New Insights

The researchers then go on to describe the next stages of research, such as deep DNA sequencing of variants, which is now becoming more affordable and will hopefully yield greater insights.

"The kind of research we've been doing now, in the last four or five years, is going to contribute greatly to that information. We are moving in a direction of more and more patients having more and more sequenced data available for clinical use, providing a whole new set of opportunities for research to translate the associations into treatments, prediction, and prevention," says O'Donnell.

And the pace of application will really depend on the pace of subsequent research, he stresses. But he reiterates his belief that this will be much quicker than with other discoveries in the past: "A decade or two is not a very long time."

The authors have no relevant conflicts of interest.


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