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UNC Analysis Finds Beta1-AR Alleles Impact Survival in Patients Treated with Beta-Blockers


This article was originally posted March 29.

By Turna Ray

CHICAGO – A recent analysis of genotype and clinical data from more than 700 heart failure patients found that individuals who are homozygous for the wild-type allele Ser49 in the beta 1-adrenergic receptor gene experienced prolonged survival when they received treatment with beta-blockers compared to Ser49 homozygotes who didn't receive such treatment.

The study, led by researchers from the University of North Carolina, Chapel Hill, also found that carriers of one or two copies of the Gly49 allele in the beta1-AR gene did not experience a survival advantage when treated with beta-blockers compared to Gly49 carriers who didn't receive such drugs.

Beta-blockers inhibit beta-adrenergic substances that regulate the nervous system of the heart and are often prescribed to control high blood pressure, to manage irregular heart rhythms, and to treat heart failure patients. There are several beta-blockers on the market approved by the US Food and Drug Administration, including AstraZeneca's Toprol XL and GlaxoSmithKline's Coreg.

Based on data from past studies, UNC researchers Jasmine Talameh, Kirkwood Adams, and others hypothesized that Ser49 allele status "will be associated with beta-blocker survival benefit in a large, heterogeneous, US heart failure population," said Talameh, who presented data from this study at the American College of Cardiology meeting here last week.

Study investigators reviewed beta-blocker use and survival for heart failure patients enrolled in the United Investigators to Evaluate Heart Failure Biomarker Registry from 2000 to 2002. The current analysis involves more than 700 patients in the registry for whom there was information on beta-blocker use, survival, and genotype.

"The UNITE-HF DNA Registry was started by Kirkwood in 1999 as a way to promote clinical registry, biomarker, and genomic research in heart failure," Talameh said during her presentation. "These prospective, multicenter, observational registries were designed to study medication use, long-term outcomes, and the genomics of heart failure patients seen in US heart failure specialty clinics."

Patients in the registry had a history of heart failure and could have been asymptomatic at the time they were enrolled. According to Talameh, the majority of patients in the registry had received Coreg and Toprol.

Study investigators used mass spectrometry to genotype patients for the Gly49 and Ser49 alleles in the lab of Howard McCleod, director of UNC's Institute for Pharmacogenomics and Individualized Therapy. During the follow-up period, researchers collected patients' clinical information at the study sites and then periodically with the Social Security Death Index.

Among the study participants, 68 percent were Ser49 homozygous and 32 percent were Gly49 carriers. Using the Social Security Death Index, researchers found that more than 340 patients died after an average follow up of seven years, of which 52 percent were Gly49 carriers and 47 percent were Ser49 homozygous.

The data show that heart failure patients in the registry, irrespective of genotype, experienced a survival benefit when they receive beta-blocker treatment. When patients were differentiated by genotype, Ser49 homozygous patients who were treated with beta-blockers experienced a survival advantage over Ser49 homozygotes who didn't receive beta-blockers, Talameh explained. "However survival was not prolonged when comparing beta-blocker-treated Gly-carriers versus beta-blocker-untreated Gly-carriers," she added. The study findings were independent of race.

Talameh further highlighted that during the follow-up period, the survival curves remained separate for the Ser49 homozygotes and Gly49 carriers. "The adjusted genotype-beta-blocker interaction p-value is 0.004, indicating the beta-blocker benefit is significantly different among Ser49Gly genotypes," she pointed out in her presentation.

This registry study shows that "patients with higher adrenergic activity genotype, which are the Ser49 homozygotes, are having a better response to beta-blockers with an adjusted hazard ratio of 0.5," she added. Meanwhile, in "patients with the lower adrenergic activity genotype, which are the Gly49 carriers … beta-blocker treatment was not significantly associated with decreased mortality."

If validated, "we think this finding could be potentially useful for beta-blockers currently on the market." Talameh told PGx Reporter.

The strengths of the trial included the lengthy follow-up performed by researchers and the diverse patient cohort. The trial was limited by its registry design, non-randomization, having a single cohort, and lack of outcome data.

"We plan to publish this finding prior to validating it in another cohort because we are currently exploring existing DNA heart failure banks for validation," Talameh said. "Also, [lead study investigator] Adams is considering starting another heart failure DNA bank to validate this finding."

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