An evaluation of the beta‐1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT‐HF sub‐study

Abstract

Background: The Glycine389 variant of the beta-1 adrenergic receptor (b1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant. Aims: 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 b1AR 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 CRyXL 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, RRs0.94; confidence intervals (CI), 0.69-1.29 (Ps0.72). This is in contrast to the highly significant benefit of Metoprolol CRyXL observed in this sub-study population, RRs0.60; CI, 0.44-0.83 (Ps0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CRyXL. Conclusion: In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortalityymorbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism.

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

“…67 A DNA bank was also established in MERIT-HF, and DNA from 600 patients was analyzed. 165 When outcomes for metoprolol CR/XL were examined by ␤ 1 389 Arg/Gly genotypes, there was no evidence of any differentiation of effect for the all-cause mortality/heart failure hospitalization end point; within the metoprolol group, the hazard ratio for ␤ 1 389 Gly carriers versus Arg/Arg was 0.93 (0.62, 0.40; Pϭ0. 74) and in the placebo group, 1.0 (0.61, 1.64; Pϭ0.99).…”

“…74) and in the placebo group, 1.0 (0.61, 1.64; Pϭ0.99). 165 It could be argued that differences in enrollment criteria between BEST and MERIT-HF may have influenced these results. However, Figure 7B gives results in ␤ 1 389Arg/Gly genotypic subgroups in a cohort of BEST patients who were selected for the MERIT-HF/CIBIS-II enrollment criteria, 86 the same as for the "BCG" group in Figure 5D.…”

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…However, negative studies, including larger, well-powered investigations, predominate suggesting that rs1801253 cannot reliably predict antihypertensive response, rate control, or heart failure outcomes 11,17,[53][54][55][56][57][58] .…”

Pharmacogenomics of Adrenergic Receptors; from Hypertension to Heart Failure

“…on the inter-individual variability in the risk of all-cause mortality or hospitalization [47]. Sehnert et al also revealed that Arg389Gly did not significantly influence survival in metoprolol-treated or carvedilol-treated HF patients [48].…”