A study published in the journal Circulation Research revealed that two specific mutations in a particular gene decrease the risk of myocardial infarction. The gene in question is the DBH (dopamine beta-hydroxylase) gene, and the study is entitled, “Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity.”
The DBH gene encodes an enzyme responsible for the chemical conversion of dopamine to norepinephrine, both hormones and neurotransmitters crucial to the central nervous system functioning.
“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,” said the study’s senior author Dr. Wolfgang Sadee in a news release.
The team analyzed genetic variants that resulted in a decrease in gene expression in data from three independent clinical cohorts. It was observed that patients who had the two particular variants in the DBH gene exhibited a two- to five-fold lower risk of suffering myocardial infarction. On the other hand, a single DBH mutation had no detectable or at best a minimal effect on the risk of heart attack. Interestingly, around 20 percent of the population was estimated to carry both the mutations.
Norepinephrine is known to over-stimulate the heart, so the control of this hormone is essential for the treatment of heart failure. The genetic combination found lowers DBH expression, and subsequently the synthesis of norepinephrine. On the other hand, beta-blockers block the activation of the gene targeted by norepinephrine 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,” noted Dr. Sadee. “Do they benefit from beta blockers? Maybe not.”
The role of the neurotransmitter dopamine in the brain is well understood; however, researchers recently found that the DBH genetic mutations had robust effects on the liver and lung tissues, rather than in the brain where the clinical significance of the mutations was minor.
“I decided to look in liver tissue and saw these really large genetic effects, which we then thought were representative of the effects in the periphery as a whole,” said Dr. Barrie, the lead author of the study. “The best thing about this study is we were able to use human tissue samples and do molecular genetic studies to identify which specific variants were important, and then we used other existing databases to validate the results clinically.”
Messenger RNA (a genetic information carrier) of the DBH gene was detected in the liver, an observation that according to Dr. Sadee “was the antithesis of everything we’ve known because DBH is supposed to be made only in neurons,”
“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.”
Since the newly-discovered mutations have an effect on norepinephrine production in several organs, they could also play a role in other conditions or disorders. In asthma for example, norepinephrine is required to open the blocked airways in the lung, so a decrease in DBH expression could represent a risk factor for this respiratory condition as it would result in a decrease in norepinephrine levels.
“Norepinephrine has a huge impact on the body on all levels — metabolic effects, a possible association with body mass index, diabetes, you name it,” explained Dr. Sadee. “That’s why this is important.”
