An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study.
BACKGROUND
The Glycine389 variant of the beta-1 adrenergic receptor (beta1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant.


OBJECTIVE
The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers.


METHODS
We identified the genotype at amino acid 389 of the beta1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes.


RESULTS
The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69-1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44-0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL.


CONCLUSIONS
In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism.
White
Hazel L
HL
Institute for Cardiovascular Research, University of Leeds, Leeds, UK. hlwhite@doctors.org.uk
de Boer
Rudolf A
RA
Maqbool
Azhar
A
Greenwood
Darren
D
van Veldhuisen
Dirk J
DJ
Cuthbert
Richard
R
Ball
Stephen G
SG
Hall
Alistair S
AS
Balmforth
Anthony J
AJ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000368:Aged; D001120:Arginine / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*
D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D001120:Arginine; D008790:Metoprolol; D005998:Glycine