Lack of association between adrenergic receptor genotypes and survival in heart failure patients treated with carvedilol or metoprolol.
OBJECTIVE
This study investigated the role of adrenergic receptor genetics on transplant-free survival in heart failure (HF).


BACKGROUND
Discordant results exist for genetic associations between adrenergic receptor alleles and end points of beta-blocker response in HF patients.


METHODS
We identified 637 patients enrolled in 2 U.S. cardiovascular genetic registries with HF and left ventricular systolic dysfunction who were discharged on beta-blocker, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), and diuretic medications. End points were determined through the national Social Security Death Master File and transplant records. We genotyped 5 polymorphisms in 3 genes: ADRB1 (S49G, R389G), ADRB2 (G16R, Q27E), and ADRA2C (Del322-325) using 5' nuclease assays and performed a multivariable clinical-genetic analysis.


RESULTS
A total of 190 events (29.8%) occurred over a median follow-up of 1,070 days. Multivariable analysis showed a significant effect of 4 clinical factors on survival: age (p = 0.006), gender (p = 0.005), ejection fraction (p = 0.0002), and hemoglobin (p = 0.00010). There was no significant effect of the polymorphisms or haplotypes analyzed on survival.


CONCLUSIONS
Genotypes and haplotypes of ADRB1, ADRB2, and ADRA2C did not significantly affect survival in metoprolol-treated or carvedilol-treated HF patients in this study. These results complement the findings of 2 similarly designed previous studies, but do not replicate an association of ADRB2 haplotypes and survival. All 3 studies differ from a survival benefit reported for bucindolol-treated homozygous ADRB1 R389 individuals. This may be attributable to a drug-specific interaction between genotype and outcome with bucindolol that does not seem to occur with metoprolol or carvedilol.
Sehnert
Amy J
AJ
CardioDx, Inc., Palo Alto, California 94303, USA. asehnert@cardiodx.com
Daniels
Susan E
SE
Elashoff
Michael
M
Wingrove
James A
JA
Burrow
Christopher R
CR
Horne
Benjamin
B
Muhlestein
Joseph B
JB
Donahue
Mark
M
Liggett
Stephen B
SB
Anderson
Jeffrey L
JL
Kraus
William E
WE
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use*; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011412:Propanolamines / Q000627:therapeutic use*; D011941:Receptors, Adrenergic / Q000235:genetics*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics
C547774:ADRA2C protein, human; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D011941:Receptors, Adrenergic; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol; D008790:Metoprolol