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

Abstract

Introduction: Heart failure (HF) is understudied among women; especially, genomic evidence implicating shared or unique mechanisms of HF with respect to reduced or preserved ejection fraction (HFrEF, HFpEF) is lacking across ethnic populations of women.Prior genome-wide association studies (GWAS) have identified approximately 30 suggestive genetic variants for HF, although none have been specifically linked to HFrEF or HFpEF. Objectives:We aimed to define, replicate, and annotate genetic variants to HFrEF, HFpEF, or both, as well as to investigate potential biological mechanisms underlying HFrEF and HFpEF among African American (AA) and European American (EA) women in three wellcharacterized, high-quality prospective cohorts, the Women's Health Initiative (WHI) study, the Jackson Heart Study (JHS), and the Framingham Heart Study (FHS).Methods: GWAS analysis on HFrEF and HFpEF were first performed among 7,982 AA and 4,133 EA in the WHI, followed by pathway analysis employing two independent methodological platforms (GSA-SNP and Mergeomics) curating KEGG, Reactome, and 3 BioCarta pathway databases. GWAS signals and biological pathways identified using the WHI were replicated in the JHS and FHS. For all replicated pathways, we performed crossphenotype and cross-ethnicity validation analyses to examine shared pathways between HFrEF and HFpEF, and phenotype-specific pathways, across ethnicities. We further prioritized key driver genes for HF according to specific pathways identified. Results:We validated one previously reported genetic locus and identified six new ones, among which one locus was allocated to HFrEF and five to HFpEF. Additionally, we defined five biological pathways shared between HFrEF and HFpEF and discovered six HFpEFspecific pathways. These pathways overlapped in two main domains for molecular signaling: 1) inflammation and 2) vascular remodeling (including angiogenesis and vascular patterning),involving key driver genes from collagen and HLA gene families. Conclusions:Our network analysis of three large prospective cohorts of women in the United States defined several novel loci for HF and its subtypes. In particular, several key driver genes reinforce the mechanistic role of inflammation and vascular remodeling in the development of HF, especially HFpEF. Given that therapeutic strategies developed for left ventricular dysfunction have had limited success for HFpEF, several new targets and pathways identified and validated in this study should be further assessed in risk stratification as well as the design of potential new HF interventions.

Inflammation and heart failure: a two-sample Mendelian randomization study

“…In addition, differences in mechanistic pathways in the development of heart failure with preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF) should be determined 51 . To this date, only one small GWAS on heart failure subtypes is available 52 . Unfortunately, due to lack of power, we could not stratify our Mendelian randomization analyses for HFrEF and HFpEF.…”

“…51 To this date, only one small GWAS on heart failure subtypes is available. 52 Unfortunately, due to lack of power, we could not stratify our Mendelian randomization analyses for HFrEF and HFpEF. Another possible explanation for our null findings is that C-reactive protein, one of our variants that did not suffer from weak instrument bias, reflects the acute phase of inflammation instead of low-grade inflammation, 53 and the latter is thought to be more important in the development of heart failure.…”