Biological Pathways and Gene Networks Link Inflammation and Vascular Remodeling to Both Heart Failure with Preserved and Reduced Ejection Fraction in Women across Ethnicities

摘要: Abstract Introduction Heart failure (HF) is understudied among women; especially, genomic evidence implicating shared or unique mechanisms of HF with respect to reduced preserved ejection fraction (HFrEF, HFpEF) lacking across ethnic populations women. Prior genome-wide association studies (GWAS) have identified approximately 30 suggestive genetic variants for HF, although none been specifically linked HFrEF HFpEF. Objectives We aimed define, replicate, and annotate HFrEF, HFpEF, both, as well investigate potential biological underlying HFpEF African American (AA) European (EA) women in three well-characterized, high-quality prospective cohorts, the Women’s Health Initiative (WHI) study, Jackson Study (JHS), Framingham (FHS). Methods GWAS analysis on were first performed 7,982 AA 4,133 EA WHI, followed by pathway employing two independent methodological platforms (GSA-SNP Mergeomics) curating KEGG, Reactome, BioCarta databases. signals pathways using WHI replicated JHS FHS. For all pathways, we cross-phenotype cross-ethnicity validation analyses examine between phenotype-specific ethnicities. further prioritized key driver genes according specific identified. Results validated one previously reported locus six new ones, which was allocated five Additionally, defined discovered HFpEF-specific pathways. These overlapped main domains molecular signaling: 1) inflammation 2) vascular remodeling (including angiogenesis patterning), involving from collagen HLA gene families. Conclusions Our network large cohorts United States several novel loci its subtypes. In particular, reinforce mechanistic role development especially Given that therapeutic strategies developed left ventricular dysfunction had limited success targets this study should be assessed risk stratification design interventions.