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Abstract: TH-OR14

Association of Genetically Predicted FGF23 with Heart Failure: A Mendelian Randomization Study

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Robinson-Cohen, Cassianne, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Pike, Mindy, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Multiple observational studies provide evidence of the role of FGF23 in the pathophysiology of heart failure, among individuals with CKD and in the general population. However, these studies suffer from many potential biases, e.g.confounding and reverse causation, limiting their ability to robustly identify causal associations. Mendelian randomization (MR) has emerged as a powerful study design to provide evidence supporting or refuting causality.

Methods

We performed a two-sample MR study to assess the causal association of FGF-23 with overall heart failure and heart failure subtypes. Instrumental variables were defined as independent SNPs associated with FGF23 genome-wide: rs17479566, rs11741640, rs9925837, rs17216707, and rs2769071. Summary-level data from the HERMES consortium and individual-level data from BioVU, was used to examine associations of the 5 SNPs with incident heart failure and subtype. We additionally developed an eGFR polygenic risk score based on CKD-GEN summary statistics, composed of SNPs associated with eGFR at p<5 x 10-3, and dichotomized the eGFR PRS at one SD below the mean.

Results

We found that genetically increased circulating FGF23 was significantly associated with higher risk of heart failure overall and with heart failure with preserved ejection fraction among individuals with genetically-predicted low eGFR (Table). Elevated FGF23 was not associated with reduced ejection fraction heart failure or preserved ejection fraction among individuals with higher genetically-predicted eGFR.

Conclusion

Our results provide evidence supporting a causal association between FGF23 and heart failure, particularly preserved ejection fraction heart failure, among individuals with low eGFR.

Mendelian Randomization Estimates for the Effect of FGF23 on Heart Failure and Subtypes
Outcome and data sourceNumber of HF EventsMR Estimate
  Hazard Ratio (95%CI)P-value
Heart failure, HERMES47,3091.25 (1.01, 1.55)0.039
Preserved EF, BioVU   
Overall12,9001.23 (0.88, 1.72)0.236
eGFR PRS <-1 SD2,1882.98 (1.31, 6.77)0.009
eGFR PRS > -1 SD10,7121.02 (0.71, 1.48)0.908
Reduced EF, BioVU   
Overall2,9280.89 (0.44, 1.83)0.760
eGFR PRS <-1 SD4860.43 (0.08, 2.34)0.326
eGFR PRS > -1 SD2,4421.04 (0.47, 2.28)0.923
    

Funding

  • NIDDK Support