Clinical and genetic modifiers of long-term survival in heart failure.
OBJECTIVE
This study sought to identify genetic modifiers of beta-blocker response and long-term survival in heart failure (HF).


BACKGROUND
Differences in beta-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 beta-blocker. Each was genotyped for beta1-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). beta-blocker treatment increased survival in Caucasians (log-rank p = 0.00038) but not African Americans (log-rank p = 0.327). Among patients not taking beta-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 beta-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 beta-adrenergic receptor signaling pathway gene polymorphisms, rather than race, are the major factors contributing to apparent differences in the beta-blocker treatment effect between Caucasians and African Americans; proper evaluation of treatment response should account for genetic variance.
Cresci
Sharon
S
Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kelly
Reagan J
RJ
Cappola
Thomas P
TP
Diwan
Abhinav
A
Dries
Daniel
D
Kardia
Sharon L R
SL
Dorn
Gerald W
GW
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D001741:Black or African American; D000368:Aged; D015331:Cohort Studies; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D044465:White People
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human