The journal Nature has a series of opinion articles and two news articles on the subject.  All are available online free of charge.  There are also other human genome related materials available at The Human Genome at Ten.

Researchers working at an NHGRI-supported large-scale sequencing center./The Broad Institute of MIT and Harvard/NHGRI multimedia gallery

• Has the revolution arrived? – Francis Collins
• Multiple personal genomes await – J. Craig Venter
• Point: Hypotheses First – Robert Weinberg
• Counterpoint: Data first – Todd Golub
• Life is complicated – Erika Check Hayden
• The human race – Alison Abbott

The British Medical Journal features a debate between two scientists over whether modern genetics is “blind alley.”  These articles are also available free of charge.

• Is modern genetics a blind alley? Yes – James Le Fanu
• Is modern genetics a blind alley? No – D J Weatherall

It’s not just the anniversary of the draft sequence that looms.  DNA Day, which was created in 2003 by a congressional resolution to celebrate the completion of the Human Genome Project and the 50th anniversary of the description of the double-helix structure of DNA by James D. Watson and Francis H.C. Crick, is coming up on April 25^th.  To accommodate classroom schedules, many events will be taking place on Friday, April 23^rd.

We’ll be rounding up a listing of DNA Day activities in the coming week or so, but you can start your preparations by checking our listing of fun DNA activities.

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Today the National Institutes of Health (NIH) announced its plans to create a public database in which genetic test providers will voluntarily deposit information about their services that can then be searched by researchers, consumers, health care providers, and others. The aim of this Genetic Testing Registry, which is expected to be launched in early 2011, is to enhance access to information about the availability, validity, and usefulness of genetic tests.

“The need for this database reflects how far we have come in the last 10 years,” said NIH Director Francis S. Collins, M.D., Ph.D., in a press release. “The registry will help consumers and health care providers determine the best options for genetic testing, which is becoming more and more common and accessible.”

“We welcome the news of the Genetic Testing Registry,” said 23andMe co-founder Anne Wojcicki in response to the announcement.  “23andMe has always been committed to providing individuals with the information they need to make the most of their own genetic information.  We look forward to working with the NIH on this project.”

More information about the Genetic Testing Registry is available from the National Center for Biotechnology Information here.  Comments and questions can be submitted from this page.  There is also a list of background reading materials.

Francis Collins has done several interviews in the past few weeks where he has discussed the role of genetics in health care, now and in the future. A quick video interview with the Washington Post can be seen here.  An hour long interview he did on the Diane Rehm show is available here.

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Medco Health Solutions, Inc., announced this week that it will conduct a clinical trial to assess whether clopidogrel bisulfate (Plavix®, Bristol-Myers Squibb and Sanofi-aventis) is just as effective as the newer drug prasugrel (Effient™, Eli Lilly and Company) in people who lack a genetic variation that inhibits their metabolism of clopidogrel. This new research has important implications for both patient safety and health care costs.

Both clopidogrel and prasugrel are anti-platelet medications that reduce the ability of blood to form clots. The drugs are used to reduce the risk of a heart attack and stroke in people who have suffered from a recent cardiovascular event, and in those who have peripheral artery disease, unstable angina or a stent.

Variations in the CYP2C19 gene that prevent clopidogrel from being converted into its active form in the body have been shown to prevent patients from receiving the drug’s full benefit. People with these gene variations who are taking clopidogrel may be at a higher risk for heart attacks, strokes and death from cardiovascular causes than those whose genetics allow them to metabolize the drug.

(Prasugrel is metabolized through a different biological pathway than clopidogrel, and is not affected by CYP2C19 variants.)

23andMe customers can see their data for several important CYP2C19 variations in the ‘Clopidogrel (Plavix®) Efficacy’ Clinical Report.

Medco’s study will assess patients’ rates of nonfatal heart attacks, nonfatal strokes and cardiovascular deaths after six months of treatment with either clopidogrel or prasugrel. Researchers will be looking to see if there is any difference between those patients who are taking clopidogrel, and whose genetics predict that they should be able to metabolize it—and those patients who are taking prasugrel.

“Plavix is going generic in 2011 and if found to be equally effective as Effient for patients who have a normally functioning version of the CYP2C19 gene, the study provides the evidence that would allow these patients to opt for a lower cost treatment,” said Medco’s chief medical officer Dr. Robert Epstein in a press release.

Former U.S. Secretary of Health and Human Services Michael O. Leavitt was quoted in the Medco press release as saying, “Studies like this are necessary to show how innovation can derive greater value from what we spend on health care.  A simple test can identify a drug’s ability to work for a particular patient or point them to another one that could provide a better outcome. Personalized medicine is the new frontier in making medication safer and more effective. What we learn from this study, and others like it, will save lives and money.”

Patients aren’t the only ones who would save if Medco’s research shows that the soon-to-be generic clopidogrel is an effective choice for them. An Associated Press story notes that generic drugs are more profitable for Medco than higher-priced brand name products.

Comparative effectiveness research has received a lot of attention in the United States health care debate lately.  Some worry that it will result in policies that are not in patients’ best interests.

“We need to be mindful of the goal of comparative effectiveness research and not lose all that we have gained in understanding how individuals differ and how that could be factored into better diagnostics and preventive strategies,” said National Institutes of Health (NIH) director Francis Collins, speaking at a recent American Association for the Advancement of Science forum on personalized medicine.

Collins recommended that genetic factors be included in comparative effectiveness research (as is the case in Medco’s study), to make sure that treatments that work for specific groups of patients are not “lost in the wash by considering everybody equivalent.”

The Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes Study (GeCCO) is part of Medco’s “Genetics for Generics” program and is registered with the NIH.

Related Spittoon Posts:
More Evidence that Genetics Can Reduce the Efficacy of Anti-Clotting Medication Clopidogrel
SNPwatch: Genetic Variants May Reduce Ability of Anti-Clotting Drug Clopidogrel to Prevent a Second Heart Attack

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In 2005 two well-known human geneticists, Francis Collins and Thomas Gelehrter, made a bet: Collins wagered that by the 2008 American Society for Human Genetics meeting, genomewide association studies would have led to the discovery of at least four “validated – not just guessed at” susceptibility variants for at least five common diseases.

Collins won his bet (and hopefully his beer) – by a margin of more than 200 variants.  According to the Human Genome Epidemiology Network, there have been 328 genomewide association studies published to date, and there is no sign of a slow down (as any devotee of SNPwatch knows). This type of research has clearly been successful. But how useful are the variants they identify?

There are two directions from which to consider this question. One is to ask whether the common variants found in genomewide association studies add to science’s understanding of the biology of various common diseases, as well as medicine’s ability to treat them.  The other is to ask whether the results of genomewide association studies have made it possible to predict individual genetic risk for various diseases.  Three opinion pieces, each with a different perspective, address these questions in the New England Journal of Medicine this week.

David Goldstein, director of the Center for Human Genome Variation at Duke’s Institute for Genome Sciences and Policy, doesn’t doubt the veracity of variants found in genomewide association studies.  But he does think that it’s time for geneticists to take a new approach.

“I believe attention should shift from genome scans of ever larger samples to studies of rarer variants of larger effect,” he writes in his NEJM commentary.

Goldstein says continued use of genomewide association approaches that look for common variants associated with common diseases and traits will ultimately lead to an unwieldy number of variants, each with vanishingly small effect sizes. For example, after making some assumptions he calculates that approximately 93,000 common variants could be needed to explain 80% of the population variation in height.

But variants with small effects can be biologically informative, argues Joel Hirschhorn, a Harvard genetics professor, in the second NEJM Perspective.  For example, genomewide association studies have identified variants associated with type 2 diabetes, high cholesterol and low bone density that are located in genes targeted by drugs already approved by the FDA for the treatment of these conditions.

“Each of the associated variants at a drug-target locus explains less than 1% of phenotypic variation in the population, demonstrating that small effect sizes do not preclude biologic importance,” he writes.

The discovery of variants with small effect sizes can also point scientists in the direction of new avenues for drug research, says Hirschhorn.  Genomewide association studies of age-related macular degeneration and Crohn’s disease have both revealed new mechanisms of disease that are now being pursued as therapeutic targets.

In the final NEJM Perspective, Peter Kraft and David Hunter from the Harvard School of Public Heath address genomewide association studies from the point of view of risk prediction.  They argue that while reliable risk predictions may be possible someday, testing for susceptibility based on common variants is currently premature for most conditions.  Like Goldstein, they note the small effect sizes associated with many of the common variants found so far.

“These factors suggest that many, rather than few, variant risk alleles are responsible for the majority of the inherited risk of each common disease….Estimates of risk based on established locus associations are therefore likely to change substantially in the next few years [as more variants are found],” Kraft and Hunter write.

Hirschhorn has a more optimistic view of the value of the variants identified through genomewide association studies.  He maintains throughout his article that the point of doing these studies is not risk prediction, but does say that it is likely that for some diseases, useful predictive information will emerge.  In fact, for some diseases the variants found to-date already give as much information to clinicians as other routinely used measures.

“For several diseases, associated variants already explain 10 to 20% or more of heritability, a magnitude that is similar to the proportion of risk explained by nongenetic tests in widespread clinical use (such as levels of low-density lipoprotein cholesterol or prostate-specific antigen),” Hirschhorn writes.

Hirschhorn goes on to argue that it is not how of much a disease’s genetics a variant or collection of variants explains, but how this information can shift the cost-benefit ratio of available clinical interventions.

“For diseases without potential therapies, even perfect prediction might not be clinically useful.  By contrast, for diseases with effective preventive measures that are too costly or for which the risk-benefit balance is nearly neutral, small increments in predictive power could help effectively target preventive efforts, with substantial clinical impact,” he writes.

Looking back at that 2005 bet between Collins and Gelehrter, it’s clear that not even the biggest names in the field could imagine just how far human genetics would come in such a short amount of time.  There’s no disputing that the study of common DNA variants has pushed science forward. And as new technologies and methods are developed, we’re sure to see even more progress.  We here at 23andMe hope to be a part of some of those new discoveries.

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