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Team IDs Mutation That Mimics Effects of Beta Blockers in Blacks With Heart Failure

Results from a multi-site prospective study have shown that a variant of the GRK5 gene can prolong survival in African Americans with heart failure.
The study, conducted by researchers at the University of Maryland and Washington University in St. Louis, reported that African American heart failure patients that carry the GRK5-Leu41 variant are naturally protected against death and the need for a heart transplant.
This “genetic beta blockade” emulates the function of beta-blockers, and thus, those who have it may not need treatment with this class of drugs, according to the paper, authored by Washington University's Gerald Dorn and colleagues.
“Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and [beta]-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia,” the study authors wrote in a paper published this week in Nature Medicine.
While the presence of the GRK5-Leu41 variant did not prevent heart failure in these patients, “those with the variant who had heart failure were just as protected as those without the variant who were on beta-blockers,” the researchers found.
They also found that the variant appears to be more common in African Americans than in Caucasians, and that patients carrying the variant who were given beta-blockers “did not experience additional benefits from the medications because their own 'genetic beta blockade' was already protecting them.”
Researchers from the University of Cincinnati College of Medicine and the University of Michigan also participated in the study, which was funded by a Specialized Centers of Clinically Oriented Research grant from NIH's National Heart, Lung, and Blood Institute.
Stephen Liggett, a study co-author and the director of the cardiopulmonary genomics program at the University of Maryland, told Pharmacogenomics Reporter this week that although the research is at an early stage, the researchers who conducted the study are interested in eventually developing a diagnostic that would help doctors personalize heart failure therapy.
This “discovery adds to the accumulating evidence that genetic differences contribute to the way people respond to medications, and should encourage the use of genetic testing in clinical trials to identify people who can benefit from therapy tailored to their personal genetic makeup,” the researchers said in a statement.
The Study
Initially, the researchers identified the GRK5-Leu41 variant by taking genetic profiles of more than 2,000 volunteers in Cincinnati, Kansas City, and Atlanta, including Americans of European descent and African Americans. One group of patients had heart failure, a second group had ischemia, and a third group comprised healthy controls.
In order to understand the genetic variation, the researchers created cell lines and developed genetically altered mice to predict how the gene functions in humans. They discovered that “the genetic variant acts in a way that is identical to beta-blocker drugs, reducing the impact of adrenalin that forces the heart to work harder,” the researchers said in a statement. “In an experimental model, the variant protected the mice from developing heart failure after exposure to a substance similar to adrenaline.”
Following this phase, the researchers then launched a multi-site, prospective study that followed 375 African Americans with heart failure for an average 2.5 years. In the study, conducted at the University of Cincinnati, some patients were on one of two commonly prescribed beta-blockers, carvedilol or metoprolol, while others were not on beta-blockers.

"In this case, it seems that this genetic variation is a good thing, mimicking drugs that are frequently used to treat heart failure.”

“There was no difference in outcome among GRK-Leu41 subjects with heart failure with or without beta-blocker treatment (hazard ratio, 0.78, 95 percent confidence interval, 0.35-1.7, P=0.53),” the authors wrote in Nature Medicine.
In discovering the function of the GRK5-Leu41 variant in African American heart failure patients, the researchers were able to gain more insight into a long-standing controversy in the field about whether beta-blockers benefit this ethnic population.
"This is a significant development in our understanding of why some African American patients appear to not respond to beta-blockers in the same way as Caucasian patients," Liggett said in a statement. "In this case, it seems that this genetic variation is a good thing, mimicking drugs that are frequently used to treat heart failure.”
Additionally, the researchers found that in clinical trials the GRK5 variant occurred in 40 percent of African Americans and in about 2 percent of Caucasians. “While [the GRK5 variant] is likely to be a factor in [Caucasian] patients as well, a much larger study would be required to verify this, because the variant is so uncommon,” the study authors said.
Future Plans
A diagnostic developed from this research could enable doctors to personalize heart failure treatment by not prescribing beta-blockers to those with the GRK-Leu41 variant, thereby avoiding adverse effects associated with the treatment and reducing healthcare costs. Also, doctors may be able to make more informed decisions about how to dose patients on beta-blockers.
Typically, heart failure patients who are hemodynamically unstable and are taking beta-blockers are more prone to experience side effects associate with the drug, which include nausea, diarrhea, bronchospasm, dyspnea, hypotension, edema, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, clinical depression, and sexual dysfunction.
“In [the] case of the current finding, if you knew that you had a patient who was genetically programmed to already have a beta-blocker equivalent on board ... perhaps then beta-blockers would be one drug that the doctor would not push forward,” Liggett said.
In terms of dose adjustments, if the doctor “knew that the patient already had somewhat of a beta-blockade already on board due to this polymorphism, then perhaps other classes of drugs would be pushed to their higher limits in terms of doses,” he added.
“Our thoughts on this would be along the lines of obviously trying to give the physicians taking care of these patients, who are typically on five or six classes of drugs, some handle on which drugs are more likely to benefit the patient,” Liggett said.
According to Liggett, the research has received attention from drug and diagnostic makers, and the researchers are interested in eventually commercializing a diagnostic for this indication.
“We do have some intellectual property on this and certainly there is a big interest in heart failure, and attempting to use genetic information to tailor therapy,” he said. “So we are interested in moving forward and we have contacts.
“I can't go into a lot of detail other than to say that the whole gamut of organizations that you might think would be interested, such as biotech, diagnostic companies, and pharmaceutical companies, have all expressed an interest,” Liggett added.
Although a formal pharmacoeconomic analysis has not been conducted, the researchers’ findings could have a significant impact on reducing healthcare spending.
“We have to look at the fact that in the US at least $40 billion is being spent on treating heart failure, and that represents about 5 percent of the entire healthcare budget,” Liggett said. “So, with regards to cost savings, if one could make a relatively small impact on that then it could be translated into a not insignificant amount of money.”
According to the Heart Failure Society of America, more than 5 million people in the US have heart failure, with 550,000 new cases diagnosed each year. Fewer than half of these individuals live beyond five years after initial diagnosis, and fewer than 25 percent are alive at 10 years.
"In heart failure treatment, there is still a lot of 'one drug fits all' thinking,” Liggett said in the statement. “This variant is one of what may be many genetic variants that can be used like a 'scorecard' to guide treatment in a much more personalized way."
He added that the University of Maryland School of Medicine has multiple research studies underway to further identify by genetic underpinnings of drug response related to the G-protein coupled receptor pathway.
“Most of the diseases we deal with in terms of our group are interested in G-protein coupled receptors. And we are very keen on using genetically-altered mice and cell-lines to help us understand mechanisms of action of a particular polymorphism than going directly forward with an association study,” Liggett said. “We are open to looking at the other drugs but we do have somewhat of a pathway dependent approach.”

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