Genetic Architecture of Heart Failure with Preserved versus Reduced Ejection Fraction

Background Pharmacologic clinical trials for heart failure (HF) with preserved ejection fraction (HFpEF) have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction (HFrEF). Whether differences in the genetic underpinnings of these HF subtypes may provide insights into the disparate outcomes of these clinical trials remains unknown. Objectives We pursued genetic association analyses to compare the genetic architecture of HFpEF with that of HFrEF. Methods We created a non-Hispanic White cohort including 19,495 HFrEF and 19,589 HFpEF cases among 43,344 unclassified HF cases, and 258,943 controls without HF in the Veterans Health Administration Million Veteran Program. We then conducted genome-wide association studies of unclassified HF, HFrEF and HFpEF, followed by genetic correlation analyses and Mendelian randomization analyses of established HF risk factors with HFrEF and HFpEF. Results We found 13 loci associated with HFrEF at genome-wide significance, but only one associated with HFpEF. Among genome-wide significant loci for HFrEF, four loci were not associated with any HF risk factor. The single locus identified for HFpEF ( FTO ) is a known marker for obesity. Genetically determined associations were widely different between HFrEF and HFpEF for several risk factors including coronary artery disease, lipid levels, and pulse pressure. Conclusions The modest genetic discovery for HFpEF compared to HFrEF despite a robust sample size indicates that HFpEF, as currently defined, likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of HFpEF is paramount to better dissect the underlying genetic signals and contributors to HFpEF. Condensed Abstract We utilized a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) based on current clinical definitions, to conduct detailed genetic analyses of the two HF sub-types. We found different genetic architectures and distinct genetic association profiles of HFrEF and HFpEF suggesting differences in underlying pathobiology. Furthermore, the low yield of HFpEF genome-wide association study (GWAS) compared to similarly powered HFrEF GWAS underscores the heterogeneity of HFpEF and the urgent need for developing consensus sub-phenotyping of HFpEF to improve the discovery in genetic mechanisms and therapeutic interventions.