Researchers identify two genetic mutations that interact to lower heart attack risk

Researchers have determined that two mutations on a single gene can interact in a way that lowers the carrier’s risk for a heart attack. The variants are found in a gene called DBH, which regulates an enzyme involved in the conversion of dopamine to norepinephrine—both of which are important chemical messengers and hormones. The research is published in a recent issue of the journal Circulation Research.

When considered alone, each variant had either an undetectable or minimal effect on the gene’s effect on disease risk. But their interaction substantially reduced expression of the DBH gene, creating conditions in the body that protect against a heart attack.

The scientists compared the genetic variants causing reduction in gene expression to data from the clinical records of three groups of patients. In all groups, patients with the two variants had a two- to five-fold lower risk of having a heart attack. About 20 percent of the population carries both variants.

“Our goal is to find genetic variants in key genes that are important medically and important for designing more efficient drug therapies. We want to predict whether there is an increased risk for disease because a class of drugs is less likely to work under conditions that are genetically determined,” says Wolfgang Sadee, professor of pharmacology and director of the Center for Pharmacogenomics at The Ohio State University and senior author of the study.

The hormone norepinephrine can overstimulate the heart when it circulates in the bloodstream or is released within the heart. The interaction that lowers gene expression in turn lowers norepinephrine production. Controlling norepinephrine is important in heart failure treatment: Beta-blockers prevent activation of the norepinephrine target gene in the heart.

“The really important outcome is the suggestion that clinicians need to test people who already have reduced activity of DBH and reduced norepinephrine,” Sadee says. “Do they benefit from beta blockers? Maybe not.”