Interaction between 2 genetic mutations can lessen heart attack risk

Scientists have identified that two mutations on a single gene can interact in such a way that it reduces the risk of 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 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.

Senior author of the study, Wolfgang Sadee, at The Ohio State University said that their goal was to find genetic variants in key genes that were important medically and important for designing more efficient drug therapies. The aim was to predict whether there was an increased risk for disease because a class of drugs was less likely to work under conditions that were genetically determined.

Dopamine and norepinephrine are neurotransmitters vital to the regular function of the central nervous system, and dopamine's influence in the brain is well understood. In this case, however, the strong effects of the genetic mutations were seen in liver and lung tissue - and not in the brain.

Lead author Elizabeth Barrie, a pharmacology postdoctoral researcher at Ohio State who completed this work as a graduate student, began her investigation of the DBH gene in the brain. Effects on gene expression associated with the variants were too small to have robust clinical significance.

Until now, DBH-related production of norepinephrine was linked to 3 areas of the body: the brain, the adrenal glands and at nerve terminals in the sympathetic nervous system, which controls the body's "fight or flight" response. The presence of DBH and norepinephrine in the bloodstream has always been thought to represent a hormone-like response coming from the adrenal glands, Sadee said.

"It turned out that the message for making DBH protein - the mRNA - is transported in sympathetic neurons to target organs and expressed there at nerve terminals where norepinephrine is needed. Therefore, we can expect a large effect of the genetic DBH variants on these local events."

The research is published in a recent issue of the journal Circulation Research.