Author + information
- Received March 31, 2009
- Revision received May 11, 2009
- Accepted May 14, 2009
- Published online July 28, 2009.
- 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⁎,⁎ ()
- ↵⁎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
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, ADRB1Gly389 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 GRK5Leu41 was associated with improved survival in African Americans (HR: 0.325, CI: 0.133 to 0.796, p = 0.01). African Americans with ADRB1Gly389Gly GRK5Gln41Gln 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.
This work was funded by R01s HL087871 and HL088577, National Institutes of Health (NIH) Specialized Center for Clinically Oriented Research in Cardiac Dysfunction and Disease P50 HL077101 and P50 HL077113, and the Penn Cardiovascular Institute. This publication was also made possible by grant number UL1 RR024992 from the National Center for Research Resources, a component of the NIH and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of National Center for Research Resources or the NIH. Dr. Dries is a consultant for ARCA biopharma, Inc., and is on the Speakers' Bureau of Bristol-Myers Squibb. Drs. Cresci and Kelly contributed equally to this work.
- Received March 31, 2009.
- Revision received May 11, 2009.
- Accepted May 14, 2009.
- American College of Cardiology Foundation