Abstract: TH-OR14
Association of Genetically Predicted FGF23 with Heart Failure: A Mendelian Randomization Study
Session Information
- CKD-MBD Potpourri: Emerging Clinical and Basic Science in Mineral and Bone Disease
November 04, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
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 source | Number of HF Events | MR Estimate | |
| Hazard Ratio (95%CI) | P-value | ||
| Heart failure, HERMES | 47,309 | 1.25 (1.01, 1.55) | 0.039 |
| Preserved EF, BioVU | |||
| Overall | 12,900 | 1.23 (0.88, 1.72) | 0.236 |
| eGFR PRS <-1 SD | 2,188 | 2.98 (1.31, 6.77) | 0.009 |
| eGFR PRS > -1 SD | 10,712 | 1.02 (0.71, 1.48) | 0.908 |
| Reduced EF, BioVU | |||
| Overall | 2,928 | 0.89 (0.44, 1.83) | 0.760 |
| eGFR PRS <-1 SD | 486 | 0.43 (0.08, 2.34) | 0.326 |
| eGFR PRS > -1 SD | 2,442 | 1.04 (0.47, 2.28) | 0.923 |
Funding
- NIDDK Support