Researchers identified 46 genetic loci tied to heart failure with reduced ejection fraction (HFrEF) and three loci tied to heart failure with preserved ejection fraction (HFpEF) in a multi-ancestry study published in Nature Communications. Heart failure affects 6.7 million people in the United States, divided largely into these two subtypes with distinct genetic architectures.
The research team meta-analyzed genome-wide association studies spanning European, African, Hispanic, and Asian ancestries. The cohort comprised 38,781 HFrEF cases, 38,163 HFpEF cases, and 526,135 controls compiled from the Million Veteran Program and Vanderbilt University's DNA Databank, known as BioVU.
Investigators discovered nine novel loci for HFrEF and one novel locus for HFpEF. Four HFrEF loci were detected specifically in participants of African ancestry near the CD36, SPI1, TRIM48, and SPNS3 genes. The lead single-nucleotide polymorphisms at these four sites exhibited low risk-allele frequencies in European populations.
A wider meta-analysis examined all-cause heart failure across 200,070 cases and 2,076,466 controls. That analysis identified 136 loci, including 12 that were novel.
Gene-based tests, tissue enrichment analyses, transcriptome-wide association studies, and fine-mapping implicated vascular, metabolic, and TGF-β/Smad signaling pathways, while nominating candidate causal genes for subtype-specific and shared disease risk.
Lead authors Chang Liu, Qin Hui, and Yan V. Sun of Emory University conducted the work alongside collaborators from the Atlanta VA Healthcare System, Vanderbilt University School of Medicine, Harvard Medical School, and Japan's RIKEN Center for Integrative Medical Sciences. The study received funding from the Department of Veterans Affairs and National Institutes of Health grant P01 HL154996, and incorporated data from the FinnGen study.
