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Genetic Markers in Jeopardy

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Despite the silver bullet that genomics often promises to be for advancing disease prevention and treatment, sometimes discovering its limitations can be just as important as exploring its potential. A recent large-scale study conducted by a team of researchers at Brigham and Women's Hospital looked at the effectiveness of using genetic markers to assess cardiovascular disease risk in a clinical setting. To their surprise, the researchers found that a genetic risk score using multiple markers for cardiovascular disease offered no significant improvement in the prediction of the disease over traditional risk factors, such as total cholesterol and blood pressure levels.

The researchers developed two genetic risk scores, culled from the National Human Genome Research Institute's collection of genome-wide association study results published between 2005 and 2009. Those scores included 101 SNPs associated with cardiovascular disease, or at least one cardiovascular disease phenotype, as well as risk alleles. They then used those scores and traditional risk factors to evaluate the risk that more than 19,000 healthy white women had of developing cardiovascular disease. The women, who are part of the Women's Genome Health Study, were followed for a median of 12.3 years and, during that time, they saw 777 cardiac events.

Although the researchers found an absolute disease risk of 3 percent over 10 years in the lowest genetic risk group, and 3.7 percent in the highest risk group, the scores were not associated with cardiovascular disease risk once adjusted for traditional factors. The study, which was published in the February 17 issue of the Journal of the American Medical Association, also confirmed the importance of the role that an individual's family history of cardiovascular disease plays in prediction.

"These results were surprising because it felt like we picked up a lot of genes that are related to cardiovascular disease and risk factors, and the hope was that having found all these genes, if you combine them all together they would be useful in getting a picture of genetic risk that we could use to stratify people into different risk groups," says Nina Paynter, an instructor of medicine at Brigham and Women's. Paynter points out that in terms of evaluating the effectiveness of genetic markers in the clinical setting, this paper is specific to a complex later-in-life disease, which is very different from Mendelian diseases in which genetics play a much larger role. "But for putting [genetic markers] together for a more population-level look, it's a lot harder and less encouraging," she adds.

As far as other genomics-based approaches that might be able to match the accuracy of traditional risk factors for preventing cardiovascular disease, Paynter says it's still difficult to know which direction researchers will take. "The next level of genomic research will be both larger cohorts and -combinations so that we can find more genes and that might help. There's the sheer volume approach," she says. "The other option is looking at gene-environment interactions or gene-gene interactions and trying to get a better sense of how the different effects fit together."

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