Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery

Abstract

Background: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. Methods: We defined all-cause HF among 488,010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease (CAD) as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy (DCM) genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4,158) and echocardiographic data (n=30,201). Results: We identified 7,382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P < 1×10 −6), the majority linked to upstream HF risk factors, i.e. CAD (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2,038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in DCM (BAG3, CLCNKA-ZBTB17). DCM signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. Additionally, analyses of loss-offunction variants implicated BAG3 as a disease-susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%, OR=12.03, P=3.62×10 −5). Conclusions: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independent of clinical HF risk factors, and which are associated with subclinical left ventricular dysfunction.

Iron Deficiency: Impact on Functional Capacity and Quality of Life in Heart Failure with Preserved Ejection Fraction

“…Thus, both population aging and the increasing number of comorbidities have contributed to enlarge the number of patients with this condition over the last years [2]. However, despite its high prevalence and recent research advances, little is known about the pathophysiology and response to medical treatment compared with those patients with heart failure with reduced ejection fraction (HFrEF) [3][4][5][6][7][8]. In fact, medical therapies that have given good results in improving prognosis in patients with HFrEF, such as ACE inhibitors, beta blockers, or sacubitril/valsartan, have not elucidated conclusive results in those with HFpEF so far [9].…”

Predicting atrial fibrillation recurrence after ablation in patients with heart failure: Validity of the APPLE and CAAP‐AF risk scoring systems

“…The presence of diabetes mellitus appeared to attenuate the benefits of catheter ablation, although the effect did not reach statistical significance . As more granular genetic assessments of HF susceptibility alleles are generated by genome‐wide association studies, specific HF genotypes most likely to benefit from AF ablation could potentially be identified . New clinical variables associated with outcomes postablation in patients with HF and AF are also likely be identified from eagerly anticipated long‐term follow‐up data from patients enrolled in the CABANA study, the largest and longest prospective randomized trial of catheter ablation in AF to date …”

The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

“…The study sample included 537409 individuals of European ancestry. Summary statistics of heart failure (HF) and nonischemic cardiomyopathy (NICM) were extracted from a meta-analysis of GWAS of 488010 European participants in the UK Biobank (6504 HF cases; 1816 NICM cases) [18] Besides coronary artery disease (CAD) and (myocardial infarction)MI came from the metaanalysis of GWAS of 185,000 cases [19].…”