QUARTERLY FOCUS ISSUE: HEART FAILURE: HEART FAILURE AND GENETICS
Clinical and Genetic Modifiers of Long-Term Survival in Heart Failure
Sharon Cresci, MD*,
Reagan J. Kelly, MS ,
Thomas P. Cappola, MD, ScM ,
Abhinav Diwan, MD*,
Daniel Dries, MD, MPH,
Sharon L.R. Kardia, PhD and
Gerald W. Dorn, II, MD*,*
* Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan
Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Manuscript received March 31, 2009;
revised manuscript received May 11, 2009,
accepted May 14, 2009.
* Reprint requests and correspondence: Dr. Gerald W. Dorn II, Washington University Center for Pharmacogenomics, 660 South Euclid Avenue, Campus Box 8086, St. Louis, Missouri 63110 (Email: gdorn{at}dom.wustl.edu).
Objectives: This study sought to identify genetic modifiers of β-blocker response and long-term survival in heart failure (HF).
Background: Differences in β-blocker treatment effect between Caucasians and African Americans with HF have been reported.
Methods: This was a prospective cohort study of 2,460 patients (711 African American, 1,749 Caucasian) enrolled between 1999 and 2007; 2,039 patients (81.7%) were treated with a β-blocker. Each was genotyped for β1-adrenergic receptor (ADRB1) Arg389>Gly and G-protein receptor kinase 5 (GRK5) Gln41>Leu polymorphisms, which are more prevalent among African Americans than Caucasians. The primary end point was survival time from HF onset.
Results: There were 765 deaths during follow-up (median 46 months). β-blocker treatment increased survival in Caucasians (log-rank p = 0.00038) but not African Americans (log-rank p = 0.327). Among patients not taking β-blockers, ADRB1 Gly389 was associated with decreased survival in Caucasians (hazard ratio [HR]: 1.98, 95% confidence interval [CI]: 1.1 to 3.7, p = 0.03) whereas GRK5 Leu41 was associated with improved survival in African Americans (HR: 0.325, CI: 0.133 to 0.796, p = 0.01). African Americans with ADRB1 Gly389Gly GRK5 Gln41Gln derived a similar survival benefit from β-blocker therapy (HR: 0.385, 95% CI: 0.182 to 0.813, p = 0.012) as Caucasians with the same genotype (HR: 0.529, 95% CI: 0.326 to 0.858, p = 0.0098).
Conclusions: These data show that differences caused by β-adrenergic receptor signaling pathway gene polymorphisms, rather than race, are the major factors contributing to apparent differences in the β-blocker treatment effect between Caucasians and African Americans; proper evaluation of treatment response should account for genetic variance.
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Abbreviations and Acronyms
| | ACE = angiotensin-converting enzyme | | CI = confidence interval | | HF = heart failure | | HR = hazard ratio | | NHLBI = National Heart, Lung, and Blood Institute | | PCR = polymerase chain reaction |
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Key Words: heart failure • beta-blocker • gene polymorphism • beta adrenergic receptor • G-protein receptor kinase
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