β2 Adrenergic Receptor Genotype and Survival After an Acute Coronary Syndrome
Abstract & Commentary
By Jonathan Abrams, MD Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Synopsis: The 79 CC and 46 AA alleles studied were found to be high long term survival, further validating pharmacogenetic targeting of β blocker therapy for improving ACS results.
Source: Lanfear DE, et al. Beta-2 Adrenergic Receptor Genotype and Survival Among Patients Receiving Beta-Blocker Therapy After an Acute Coronary Syndrome. JAMA. 2005;294:1526-1533.
An interesting report form the midwest heart Institute and Washington University School of Medicine suggests that polymorphisms of b2 adrenergic receptors influence survival in ACS patients treated with a β blocker. This was a prospective cohort 3-year study of 735 ACS patients admitted to 2 Kansas City medical centers, most of whom were treated with a β blocker at discharge. All patients were evaluated by standard criteria, including ECG and troponin status. Four variations of the β1 and β2 adrenergic receptor genes were identified. Lanfear and colleagues stratified the ACS cohort into 4 genotypes of 2 common functional polymorphisms. Genotyping was carried out using conventional assays. "The 4 variants analyzed were chosen due to their frequency and the strength of evidence linking them to cardiovascular phenotypes, particularly β blocker response phenotypes." In particular, these were polymorphisms that may influence different therapeutic end points of β blocker treatment, such as blood pressure control or improvement in ejection fraction. The ADRB1 alleles had no relationship to survival. The ADRB2 genotypes did predict a differential survival over 3 years, the allele frequencies in the study were "roughly similar to that reported for the general population". Polymorphism ADRB2 79 CG genotype predicted survival, in that individuals who were homozygous for the C allele had the worst prognosis, with the best survival for those homozygous for the G allele. The Kaplan-Meier mortality rates were 16% for the homozygous C allele, 11% for the heterozygous C allele, and 6% for the homozygous G allele (P = .03), after adjustment for multiple major risk factors. Thus, the hazard ratio for CG vs CC was 0.50, and was 0.24 for GG vs CC (P = .004). No association was identified between genotype and survival among those not given a β blocker at discharge. Genotype ABRB2 46 GA was also associated with survival, with 20% 3-year mortality for the AA allele vs 10% for GA and GG, and 0.48 and 0.44 hazard ratios for GA vs AA, respectively (P = 0.02). Again, no associations were found between genotype and mortality in individuals not ischarged on a β blocker. The ABRD2 haplotype and compound genotypes were also associated with 3-year mortality. Lanfear et al conclude that this prospective pharmogenetic cohort of ACS patients demonstrated a significant association of ABRD2 genotypes with 3-year survival in individuals discharged on a β2 adrenergic blocker. The 79 G and 46 A allele homozygotes had the highest mortality. The ADBR2 79 CG polymorphism has been shown to be associated with β blocker efficacy in heart failure, comparable to the current data. Lanfear et al suggest that "impaired desensitization of the β2 adrenergic receptor may allow for a better response to β blocker therapy". The discussion emphasizes that one might be able to select patients for a β blocker in whom clinical out comes will be "especially beneficial," particularly those carrying the 79 G and 46 G alleles. They point out that this is an observational cohort study, but suggest that their population is typical for ACS. They emphasize that the no β blocker group was too small to derive any conclusions. The 79 CC and 46 AA alleles studied were found to be high, long-term survival, further validating pharmacogenetic targeting of β blocker therapy for improving ACS results.
Commentary
While much of the genetic terminology and concepts in this interesting article may be beyond the typical card-carrying cardiologist (including myself), this report is of great interest, and suggests that we are not far from using genetic interrogation to help determine which subsets of individuals may or may not respond well to a given pharmacologic agent. The β adrenergic system appears to lend itself very well to such analyses, and if these results can be confirmed in larger studies, this will be a fertile and fruitful field for investigators, as well as for the clinician. For instance, if genotyping becomes readily available, such that one can differentiate low vs high risk individuals, it would be a major medical advance.
The 79 CC and 46 AA alleles studied were found to be high long term survival, further validating pharmacogenetic targeting of b blocker therapy for improving ACS results.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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