Genetic Influence on Beta-Blocker Therapy

April 18, 2019
Tavid Westerhoff-Mason

Beta-blockers have grown in influence since their properties were first discovered in 1958. They stand as staples in modern cardiovascular disease management. However, research into their receptor pathway has shown certain genetic factors can have a tremendous influence on beta-blocker pharmacodynamics. Mutations within the targeted receptors and associated regulatory proteins can change typical responses to beta-blocker therapy. Ultimately, a simple genetic test could reveal the difference between a 2-fold response and management altering resistance.

Beta-blockers are so called because they antagonise the activation of beta-adrenergic receptors. Beta-adrenergic receptors of the β1, β2, and β3 varieties are found throughout the body The main target is the blockade of β1-receptors found primarily in the heart, creating a negative chronotropic and inotropic effect. Specific beta-blockers are selected based on their selectivity for receptors, the relative degree of antagonism, and duration of action. However, polymorphisms within the receptor protein can also change the effect of beta-blockade and may need to take into account when selecting the appropriate therapy.

β1-adrenergic receptors are G Protein Coupled receptors encoded by the ADRB1 gene. A single nucleotide polymorphism, called rs1801253, on the beta-blocker binding site can result in a receptor that binds more strongly with the drug. This complex responds more strongly than normal to blockade and is a more easily inactivated receptor and increases drug efficacy. Homozygous carriers of this ADRB1 mutation can have as much as a 2-fold increase in responsiveness to beta-blocker. This can be measured as a drop in blood pressure and increased left ventricular ejection fraction.

Beta-blocker mechanism of action
‍Figure 1: A mutation in the beta adrenergic receptor gene can lead to a stronger response to beta blocker therapy

Beta adrenergic receptor activity is managed by a group of G protein receptor kinases encoded by the GRK5 gene. A single nucleotide change in the GRK5 gene results in a protein that is much better at deactivating the beta receptor. Homozygous carriers of this mutation have two copies of this hyperactive beta receptor deactivator. The cumulative effect being an enhanced effect on the blood pressure lowering properties of beta-blocker therapy. However, patients lacking this mutation have receptors that may stay active for longer. In fact, they may respond poorly to beta-blocker treatment. This effect is so pronounced that it is suggested that this subgroup of patients be prescribed ivabradine, instead. Ivabradine inhibits the funny current. Funny current inhibition bypasses beta receptors that may be resistant to traditional therapy.

Clearly, genetics can play a major role in the choice of beta-blocker therapy. Some studies have even shown a possible role for beta-receptor polymorphisms in the development of heart failure. All this data is part of a growing collection of evidence that genetic testing for polymorphisms has an important role to play in the management of heart failure and cardiovascular disease. The next step is getting this information into the hands of physicians before the complications it could have prevented occur. Perhaps one day soon, a standard trip to a cardiologist may include a sputum sample.

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