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Thursday, January 22, 2009

A Genetic Test for Heart Disease and Cancer Risk

DNA diagnosis: Customers who order DecodeMe’s genetic tests receive the kit pictured above. The black wand is scraped against the inside of the cheek to collect cells for DNA analysis.
Credit: Decode Genetics

From car makers to cosmetic surgeons, everyone is scrambling to develop and market more economical products--and the consumer-genetics industry is no exception. DecodeMe, a division of Iceland-based Decode Genetics, launched two new services this week: a test that detects genetic variations associated with different cardiovascular diseases, and a screen that detects genetic variations linked to the risk of developing various cancers. At $195 and $225, respectively, the new tests are cheaper than Decode's genome-wide screen, which for $985 assesses genetic risk for 34 diseases and traits ranging from diabetes to male-pattern baldness. "We wanted to give people an opportunity to buy a test that would only address their needs," says Kari Stefansson, Decode's president and cofounder.

But the same question that has plagued direct-to-consumer genetic testing since its inception remains: the clinical utility of such screens. "We have not sorted out what the best approach is for dealing with prostate-cancer risk in the normal population, much less in those who are at some increased risk," says James Evans, a physician and geneticist at the University of North Carolina at Chapel Hill. He says that the same is true for other types of cancer.

The first test--deCODEme Cardio--detects eight genetic variations, known as single-nucleotide polymorphisms (SNPs), associated with the risk of heart attack, intracranical and abdominal aortic aneurysm, stroke and atrial fibrillation, peripherial arterial disease, and venous thromboempolism (clots in blood vessels). The second test--deCODEme Cancer--measures 29 SNPs associated with the risk of prostate, lung, bladder, colorectal, and breast cancers, as well as basal cell carcinoma.

The variations detected by the Decode tests clearly do increase risk of these diseases--in most cases, the link has been replicated numerous times. But they each boost risk of disease by a modest amount: typically 20 percent or less. In contrast, mutations in the BRCA1 gene, which physicians often screen for in women with a family history of breast cancer, boost a woman's risk of developing breast cancer to between three and seven times that of someone who lacks the mutation. While the latter can help physicians recommend preventative measures, such as a mastectomy, it's not yet clear how common variations of moderate effect can help shape an individual's plan for prevention or treatment of disease.

"I'm very excited that these kinds of tests will allow us to provide better care for our patients, but we need to do more work to understand exactly what the true benefits will be from this kind of testing," says David Herrington, director of the Translational Science Institute at Wake Forest University School of Medicine, in Winston-Salem, NC. This is true for any new risk-factor tests, he says, not just genetic ones.

In terms of heart disease, physicians often employ risk-prediction models, which use cholesterol, blood pressure, and other measures to predict an individual's risk of developing heart disease over the next decade and to individualize treatments. Patients classified as high risk may be prescribed an aggressive cholesterol-lowering drug regimen or be told to reduce their lipid levels to a lower target than those in a lower risk group. But studies examining whether incorporating a heart-disease-linked variant on chromosome 9 (9p21, which is used in the Decode heart test) into standard prediction models have had mixed results. "It's not yet clear that the 9p21 variants by themselves will provide a sufficiently large increment in knowledge about risk to dramatically change how we categorize people with respect to risk," says Herrington.

The different outcomes for 9p21 may be tied to different populations under study, emphasizing the need to identify who might benefit from such tests. "At the individual level--not the population level--the genomic markers may be quite helpful," says Eric Topol, director of the Scripps Translational Science Institute in La Jolla, CA. "Even [reclassifying someone] from no risk to moderate risk is an important point for an individual and his or her physician to be aware of." One case in which Topol says that specific genetic testing may be useful is for patients who have had a stroke of unknown cause: they may consider being tested for the genetic variant linked to atrial fibrillation, an abnormal heart rhythm that can increase risk of stroke.

Scientists are now starting to test whether combinations of risk factors may have a larger effect on risk prediction. In the case of breast cancer, several common genetic risk factors have already been identified. The Decode cancer test identifies eight such variants. According to Stefansson, women who carry two copies of all eight have a 50 percent risk of developing breast cancer over their lifetime.

"The National Cancer Institute recommends that women with a 20 percent or greater lifetime risk of breast cancer should have an annual image of the breast," says Stefansson. "This is an indirect way of saying it's important to identify women with a 20 percent or more risk."

But others say that it's not yet clear how to combine knowledge of multiple genetic risk factors. "We don't yet know how to combine such data in an accurate way," says Evans. Accurate estimates are especially important for patients who might choose radical prevention measures, namely mastectomy, he says.

"Such information is not now and may not ever be ready to use in a direct clinical manner, but that does not mean that it isn't incredibly important information," says Evans. "These kinds of data will tell us lots about the origins of cancer, will increase our understanding of the disease, and will surely have long-term beneficial impact on drug design and treatment."