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Genetic Variant Predicts Heart Disease Risk

A newly identified risk factor for heart disease also seems to indicate which patients will benefit from popular statin therapies.

Testing for a genetic variation could predict the likelihood that a patient will respond well to certain statins. But some researchers say it’s too soon to use the variation to determine treatment.

Heartsick: There have been many false leads in identifying risk genes for heart disease, so the burden of proof for those studies should be much higher than usually required, some experts say.

Researchers from Celera reported yesterday in the Journal of the American College of Cardiology that a single substitution in the sequence of a gene called KIF6 makes people both more susceptible to heart attacks and more responsive to certain drugs that lower cholesterol. Though there is no known biological explanation linking the variation to heart disease, the study found that it increases the risk of heart attacks and strokes by 55 percent.

Celera, the company best known for sequencing the human genome, examined 35 single-nucleotide polymorphisms (SNPs) in 30,000 patients. Of those, “KIF6 is by far the most significant,” says Thomas J. White, chief scientific officer at Celera. In fact, nearly 60 percent of the study population was found to carry the KIF6 variant. (According to the study, these findings take into account other factors, such as smoking, high blood pressure, and cholesterol levels.)

The researchers also found that carriers of the KIF6 variant responded better to the cholesterol-lowering drugs pravastatin (Pravachol) and atorvastatin (Lipitor). For example, among patients with the genetic variation, those who took pravastatin were 37 percent less likely to experience a heart attack than those who took the placebo. Those without the genetic variation who took the drug were only 14 percent less likely to experience a heart attack than those who took the placebo. Statins are big sellers for the pharmaceutical industry. In 2006, Lipitor, the world’s best-selling drug, brought in $13 billion in global sales.

“This is one of the first studies to show an interaction with therapy” and genotype, says Marc Sabatine, professor of medicine at Harvard Medical School and a coauthor on one of the papers. “That is very exciting to see.”

Surprisingly, the researchers found that KIF6 doesn’t appear to work by lowering levels of LDL or “bad” cholesterol, the standard by which drugs used to prevent heart attacks are normally measured. White says that KIF6 may instead act by stabilizing “vulnerable plaques,” which are particularly prone to triggering heart attacks.

Celera is developing a diagnostic that would test for the KIF6 variant and expects to launch it in a few months.

But some experts caution that it may be premature to introduce such diagnostic tests before there is further confirmation of KIF6’s role in heart disease.

“Even if there are beneficial results, the standard should be that you need to document that knowing the genetic information is clinically useful,” says Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital.

Coronary heart disease caused one of every five deaths in the United States in 2006, so scientists have for quite some time been on the hunt for genes linked to heart attacks.

Rapid advances in technology have made that task much easier. At the same time, many of the genetic links to heart disease identified so far haven’t held up on further analysis. At present, the only credible link is to a variant of the gene 9p21, identified last year by the Icelandic company deCODE Genetics, says Kathiresan. DeCODE offers a $200 diagnostic test for the 9p21 variant. (See “Gene Variant Linked to Heart Disease.”)

A second gene, PCSK9, also looks promising, Kathiresan adds. “Nearly everything else is in the realm of ‘possible but not definite.’”

It’s good that KIF6 has been identified as a potential risk factor in several different studies, Kathiresan says. In each of the studies, he notes, there is less than a one-in-20 probability that the finding is a result of chance, which is generally considered an acceptable threshold for statistical significance.

But because of the high possibility of false positives, the threshold for genome-wide association studies should be much higher, on the order of one in 20 million, Kathiresan says. Both the 9p21 and the PCSK9 pass that test, he says.

“The key issue here is we don’t know if these [KIF6 studies] are real results,” Kathiresan says. “You need to show that it is clinically useful, and they have not crossed that threshold.”

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