Genes dictate the color of our hair and eyes. They factor into whether we get cancer or heart disease. And, scientists increasingly recognize, they also ensure some patients will benefit from a prescription drug, while others develop adverse reactions or simply fail to respond at all.
Now University of Florida researchers have discovered that patients with heart failure can harbor genetic variations that determine whether they will tolerate the common heart drugs known as beta-blockers. In a separate study, they also determined certain genes influence whether beta-blockers successfully restore the heart to a more normal shape and size in these patients. The findings, published recently in the journal Clinical Pharmacology and Therapeutics and the journal Pharmacogenetics and Genomics, highlight the need to individualize therapy, as opposed to treating all people with a certain disease generally the same, said the studies' principal investigator Julie Johnson, Pharm.D., director of the UF Center for Pharmacogenomics.
Although diet, age, health status and the environment also shape how people respond to medications, personalizing drugs based on genetic makeup instead of taking a trial-and-error approach could lead to safer, more effective treatments, said Johnson, also a professor at UF's colleges of Pharmacy and Medicine and chairwoman of the department of pharmacy practice. Because of hereditary factors, some patients break down drugs more slowly, so the amount of a certain medication may soar to toxic levels in the body. Others metabolize drugs quickly, and never accumulate enough in the bloodstream to ease what ails them.
"In the past five to 10 years, there's really been an increased interest in understanding the role of genetics in determining how people respond to drugs," Johnson said. "The reason for that is that we know that in a group of individuals, a certain portion will have side effects, or toxicity from a drug, a certain portion will derive the benefits we want, and some won't derive any benefit. The long-term goal is to try to be able to determine that before we actually have to give them the drug."
A clearer understanding of who would benefit from beta-blocker therapy also would ensure more patients would be helped, Johnson said, citing a serious international problem with both underuse and underdosing of the drugs.
In the past five years, beta-blockers have become a standard part of the treatment for heart failure. Patients with the disorder have enlarged hearts that lose the normal heart shape and become rounder and somewhat baggy. Beta-blockers help restore the heart to a more typical shape and size and, in doing so, improve heart function. The drugs also have been shown to prolong life and reduce the rate of hospitalization for heart failure symptoms.
But patients who start taking beta-blockers must begin at very low doses that are slowly increased over a series of months. Some patients tolerate them well; others have difficulty and suffer adverse reactions such as a worsening of their heart failure symptoms. Those patients, who may experience shortness of breath, ankle swelling or fluid retention in the lungs, fatigue and reduced ability to tolerate exercise, require even more time to adjust to increasing doses, and some must switch to other medicines.
"At the moment, the consensus guidelines for treatment of heart failure are that basically everyone should get this drug," Johnson said. "I'm certainly not sitting here saying we should change those consensus guidelines, which come about because of large clinical trials and because of benefits that are shown in large clinical trials. But we know that, at an individual level, not everybody benefits from any given therapy."
So UF researchers set out to determine whether variations in an individual's genetic code might influence how well a patient tolerates beta-blockers once therapy is begun. They took blood samples from 61 heart failure patients, focusing on a particular gene called the beta-one adrenergic receptor gene, which makes a protein that beta-blockers bind to.
Differences within that gene among individuals helped predict those who were able to tolerate the drug well in the first couple months of taking it, compared with those who did not respond as favorably. Patients with either of two variants were three times more likely to require increases in heart failure medications to treat worsening symptoms after they began taking beta-blockers and required more frequent follow-up. The National Institutes of Health, Orchid Biosciences Inc. and UF funded the study, which was conducted at UF and the University of North Carolina at Chapel Hill.
"These very small, subtle differences that occur in the gene are producing enough differences in the action of the drug that we're able to see that in the way the patients tolerate the beta-blocker," Johnson said.