Assessing the role of rare pathogenic variants in heart failure progression by exome sequencing in 8,089 patients

Abstract

Most therapeutic development is targeted at slowing disease progression, often long after the initiating events of disease incidence. Heart failure is a chronic, life-threatening disease and the most common reason for hospital admission in people over 65 years of age. Genetic factors that influence heart failure progression have not yet been identified. We performed an exome-wide association study in 8,089 patients with heart failure across two clinical trials, CHARM and CORONA, and one population-based cohort, the UK Biobank. We assessed the genetic determinants of the outcomes time to cardiovascular death and time to cardiovascular death and/or hospitalisation, identifying seven independent exome-wide-significant associated genes, FAM221A, CUTC, IFIT5, STIMATE, TAS2R20, CALB2 and BLK. Leveraging public genomic data resources, transcriptomic and pathway analyses, as well as a machine-learning approach, we annotated and prioritised the identified genes for further target validation experiments. Together, these findings advance our understanding of the molecular underpinnings of heart failure progression and reveal putative new candidate therapeutic targets.