SNP to the rescue?

Can a common single nucleotide polymorphism (SNP) have sufficient impact to affect therapeutic targeting in heart disease? This possibility has recently been raised in a paper by Liggett and colleagues, who showed that a polymorphism in the β₁-adrenergic receptor (β₁AR) altered cardiac function and response to the adrenergic receptor antagonist bucindolol in human heart failure.

Clinical trials of β₁AR antagonists in heart failure have often revealed substantial interindividual variability in outcomes, which the authors considered could be due to differences in the β₁AR gene. Indeed, the Liggett group had previously found a common non-synonymous SNP that results in either Arg or Gly being encoded at amino-acid position 389 of the β₁AR. Compared with Gly-β₁AR, Arg-β₁AR displayed increased stimulation of adenylyl cyclase in transfected fibroblasts, enhanced contractility in transgenic mouse hearts and caused a larger increase in left ventricular ejection fraction after β₁AR antagonist administration in human studies.

The authors therefore set out to investigate the relevance of this SNP for β₁AR antagonist therapy in heart failure by using bucindolol, a drug that has previously failed to show efficacy in clinical trials. Ventricular tissue from failing and non-failing human hearts was used to investigate the impact of β₁AR genotype on contractile responses. In both heart types, Arg homozygotes displayed fourfold larger agonist-promoted contractility than Gly carriers. In transfected fibroblasts expressing β₁ARs of either genotype, those expressing the Arg-β₁AR displayed a substantially greater degree of noradrenaline-stimulated cAMP accumulation, and bucindolol showed a larger absolute cAMP-lowering effect in these cells compared with those expressing the Gly-β₁AR.

To understand the clinical implications of the β₁AR SNP, the authors undertook genotyping of the β₁AR allele in patients who had taken part in a large placebo-controlled clinical trial of bucindolol for the treatment of moderate and severe heart failure. Each patient cohort consisted of >200 subjects, grouped by treatment and genotype. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of heart failure. However, Arg homozygotes treated with bucindolol had an age-, sex- and race-adjusted 38% reduction in mortality and 34% reduction in mortality or hospitalization compared with placebo. In contrast, Gly carriers had no change in clinical response to bucindolol compared with placebo. The therapeutic advantage of Arg homozygotes was due to the degree of adrenergic activity that could be antagonized by bucindolol.

Although it has yet to be shown whether these results can be extrapolated to other β₁AR antagonists with differing pharmacological properties to bucindolol, this study has shown that a drug that was not efficacious in a mixed patient population displayed greater efficacy in patients of a specific genotype, and so could set the stage for genetic-based treatments in heart failure.