April 4, 2008
Gene variants found to be powerful predictors

kathiresanResearchers from the MGH Cardiology Division are taking the first steps toward using genetics to identify individuals who might benefit from earlier use of measures to prevent cardiovascular disease. A study in the March 20 New England Journal of Medicine — led by Sekar Kathiresan, MD, MGH director of Preventive Cardiology (right) — confirms that combinations of gene variants associated with cholesterol levels can signify increased risk of heart attack, stroke or sudden cardiac death.

"The prospect of personalized medicine has received much hype, but until recently, there has been little hard evidence to back up the promise," says Kathiresan. "We feel that our data supports the possibility that a panel of gene variants will be useful in preventive cardiac care. We also show that the combination of multiple variants related to cholesterol importantly contributes to the genetic risk for heart attack."

The NEJM study analyzed data from more than 5,400 adults over a 10-year period. Participants received a genotype score of 0 to 18 based on whether they had any unfavorable copies of nine cholesterol-associated gene variants. Not only did a higher score reflect more elevated LDL ("bad") cholesterol and lower HDL ("good") cholesterol levels, but those with genotype scores of 11 or higher also had a 63 percent greater risk of a cardiovascular event during the study period than did those with scores of 9 or lower.

Before this kind of information can be used to guide the care of patients, Kathiresan explains, all the gene variants associated with cardiovascular risk must be identified. Earlier this year, he and colleagues from the Broad Institute identified six new cholesterol-associated variants in a separate study published in the Feb. 1 Nature Genetics.

"A current clinical dilemma is how early to start patients on cholesterol-lowering medications like statins," he says. "Our work suggests that someday we may have a genetic test to help identify patients needing more intense pharmacological and lifestyle treatments." MGH co-investigators on both publications include Christopher Newton-Cheh, MD, of the Cardiology Division and David Altshuler, MD, PhD, of the Center for Human Genetic Research and Department of Molecular Biology.

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