Mendelian randomization and the association of fibroblast growth factor-23 with heart failure with preserved ejection fraction.

Abstract

Observational data provide compelling evidence for elevated fibroblast growth factor-23 (FGF23) as a risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Given the limitations of observational studies, uncertainties persist regarding the causal role of FGF23 in the pathogenesis of HF and HFpEF. Recently, Mendelian randomization (MR) studies have been performed to examine causal associations between FGF23 and HF phenotypes. The current review describes the methodological basis of the MR techniques used to examine the causal role of FGF23 on HF phenotypes, highlighting the importance of large-scale multiomics data. The findings from most of the MR studies indicate an absence of evidence of a causal effect of FGF23 on the risk of HF in general population settings. However, analysis using individual-level data showed a strong association between genetically-predicted FGF23 and HFpEF in individuals with a genetic predisposition to low estimated glomerular filtration (eGFR). Evidence from MR analysis suggests a causal role of FGF23 in the pathogenesis of HFpEF in low eGFR settings - a finding supported by experimental, clinical, and epidemiological data. While future MR studies of FGF23 and HFpEF could provide further evidence, randomized trials of FGF23-lowering agents could provide the most definitive answers on the association in chronic kidney disease populations.