NEW YORK – An international team led by investigators in the UK has identified dozens of new and known genetic loci with ties to heart failure (HF) and its subtypes, providing clues to the genes, pathways, tissues, and organs that contribute to the disease.
"Our findings advance our understanding of the genetic factors influencing the risk of heart failure and its subtypes," Thomas Lumbers, a researcher at University College London and Health Data Research UK and the corresponding author of a study published in Nature Genetics on Tuesday, said in an email.
For their study, Lumbers and his colleagues brought together genetic data for more than 1.9 million individuals enrolled in 42 "Heart Failure Molecular Epidemiology for Therapeutic Targets" (HERMES) consortium studies, including 153,174 individuals with HF.
Using the genotyping results, along with diagnostic data, the team went on to perform genome-wide association studies and cross-ancestry GWAS meta-analyses focused on HF and HF subtypes, including reduced left ventricular systolic ejection fraction and preserved ejection fraction forms of nonischemic etiology HF (ni-HF).
Within a group of 44,012 study participants with ni-HF, the researchers flagged 5,406 cases of "nonischemic heart failure with reduced ejection fraction" (ni-HFrEF) and 3,841 "nonischemic heart failure with preserved ejection fraction" (ni-HFpEF) cases.
"Our study focuses on HF occurring in the absence of major secondary causes, specifically, previous myocardial infarction, revascularization, congenital heart disease, and significant valvular disease," the authors explained. "By focusing on cases without these common upstream drivers, our findings highlight mechanisms intrinsic to HF, including cardio-renal mechanisms and primary cardiomyopathies."
The investigators' GWAS and GWAS meta-analyses, coupled with functionally informed fine-mapping, led to 547 potential causal variants for overall HF or specific HF subtypes, falling into 37 new and 29 known loci.
The team's subsequent phenome-wide association study, based on data spanning 294 disease-related phenotypes for 408,480 UK Biobank participants of European ancestry, pointed to ties between HF-associated loci and more than 200 clinical traits or conditions. These included phenotypic features implicated in atherosclerosis, cardiac arrythmia, toxic acetaldehyde-related enzyme activity, hypertension, and adiposity.
With a series of follow-up gene prioritization, heritability, colocalization, Mendelian randomization, and polygenic risk score analyses, meanwhile, the researchers delved into the functional effects of the risk variants in specific cell, tissue, and organ types, along with the role of potentially modifiable lifestyle factors such as smoking or alcohol consumption.
Their results pointed to more pronounced heritability for ni-HFrEF forms of HF and dialed-down heritability for ni-HFpEF. In addition, ni-HFpEF appeared to be tied to non-cardiac tissue types, particularly kidney, vascular, and metabolic tissues.
"While the heart is the primary organ through which genetic factors affect reduced ejection fraction, our analysis indicates that the kidney and other organs also play a significant role in preserved ejection fraction," Lumbers explained. "These findings provide new evidence reinforcing the concept of heart failure with preserved ejection fraction as a multisystem clinical syndrome, offering insights into its underlying biological mechanisms."
He noted that additional studies are underway in the UK and the US to continue untangling heart failure features and to devise treatment strategies, including the UK HFpEF Study, which is funded by the British Heart Foundation and the National Institute for Health Research, and a prospective study of HFpEF etiology and treatment strategies in the US.
Within that context, the current study "motivates a widening of the lens through which we consider the etiology of heart failure with preserved ejection fraction and motivates further studies," Lumbers wrote.