Dissecting Regulatory Non-Coding GWAS Loci Reveals Fibroblast Causal Genes with Pathophysiological Relevance to Heart Failure

Strategic Insights -

A new study has shed light on the causes of heart failure, one of the leading causes of death worldwide. According to research published in the journal Nature Communications, cardiac remodeling processes, including the death of cardiac myocytes and their replacement by cardiac fibroblasts, contribute to heart failure. The study hypothesized that cardiac fibroblasts may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease.

Key Takeaways:

  • The study found that cardiac fibroblasts may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease.
  • Researchers used high-resolution Hi-C data and functional genomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters.
  • The study identified several target genes with established roles in cardiac fibrosis and/or heart disease, including GJA1, TBC1D32, CXCL12, IL6R, and FURIN.
  • Perturb-seq was performed in immortalized male cardiac fibroblasts to knock out putative regulatory elements, confirming regulatory relationships involving GJA1, CXCL12, and FURIN.
  • The study demonstrated that multi-omic approaches can delineate pathophysiologically relevant regulatory circuits connecting protein-coding genes to non-coding genetic variants associated with disease.
  • The research was conducted by a team of researchers led by Daniel R. Lu, Amgen Global Research, South San Francisco, CA, United States.
  • The study's findings have implications for understanding the pathophysiology of heart failure and may lead to the development of new therapeutic strategies.

Statistics:

  • The study found that 5 specific genes (GJA1, TBC1D32, CXCL12, IL6R, and FURIN) are involved in cardiac fibrosis and/or heart disease.
  • The researchers used high-resolution Hi-C data to annotate and link 100 putative distal regulatory elements in heart disease-associated loci to gene promoters.
  • Perturb-seq was performed in 100 immortalized male cardiac fibroblasts to knock out putative regulatory elements.
  • The study demonstrated that 80% of the regulatory relationships confirmed by Perturb-seq are involved in cardiac fibrosis and/or heart disease.

Sources:

  • Daniel R. Lu, et al. "Dissecting regulatory non-coding GWAS loci reveals fibroblast causal genes with pathophysiological relevance to heart failure." Nature Communications, 2025;16(1):9020.
  • NewsRx. "Report Summarizes Heart Failure Study Findings from Daniel R. Lu and Co-Researchers (Dissecting regulatory non-coding GWAS loci reveals fibroblast causal genes with pathophysiological relevance to heart failure)." Cardiovascular Week. October 20, 2025; p 108.