LAUSR

In this issue of the journal, Angermann et al.1 provide evidence that germline common genetic variation in a neuropeptide G protein-coupled receptor functionally expressed in the brain influences clinical outcomes in heart failure with reduced left ventricular ejection fraction (HFrEF). A non-synonymous A→T single nucleotide polymorphism (SNP) in exon 3 of the neuropeptide S receptor 1 (NPSR1) gene2 that results in a gain of function Asn→Ile variant at amino acid position 1073 was associated with an increase in rehospitalization in a HFrEF study population.1 The minor allele, NPSR1 107Ile variant had been previously implicated in increased anxiety4 and stress reactivity,5 which led Angermann et al. to hypothesize that the TT or Ile107Ile genotype, present in ∼20% of the subject population, would be associated with differences in clinical outcomes and utilization of disease management interventions.1 The analysed data supported the component of the hypothesis dealing with clinical outcomes, as within the disease management arm of the study presumed increased awareness of heart failure symptoms conferred by the NPSR1 Ile107Ile genotype was transmitted into more numerous encounters with cardiologists or other specialists and more frequent rehospitalizations.1 The genotype subgroups in the Angermann et al. study1 had no important differences in baseline characteristics, and a multivariable analysis strengthened the conclusion that the NPSR1 Ile107Ile genotype is causally related to the observed clinical findings. In addition, biological3 and clinical behavioural4,5 plausibilities support this interpretation. Moreover, the Angermann et al. study1 was a ‘prospective–retrospective’ biomarker analysis,6 meaning that the hypothesis was prospectively stated prior to analysis of data generated in a previously conducted clinical study. All these factors increase the probability that the primary observation was