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Original ArticleMineral Metabolism
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Association of Genetically Predicted Fibroblast Growth Factor-23 with Heart Failure

A Mendelian Randomization Study

Elvis Akwo, Mindy M. Pike, Lale A. Ertuglu, Nicholas Vartanian, Eric Farber-Eger, Loren Lipworth, Farzana Perwad, Edward Siew, Adriana Hung, Nisha Bansal, Ian de Boer, Bryan Kestenbaum, Nancy J. Cox, T. Alp Ikizler, Quinn Wells and Cassianne Robinson-Cohen
CJASN August 2022, 17 (8) 1183-1193; DOI: https://doi.org/10.2215/CJN.00960122
Elvis Akwo
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
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Mindy M. Pike
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
2Division of Cardiovascular Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee
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Lale A. Ertuglu
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
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Nicholas Vartanian
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
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Eric Farber-Eger
3Division of Cardiovascular Medicine, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
4Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Loren Lipworth
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
2Division of Cardiovascular Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee
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Farzana Perwad
5Division of Pediatric Nephrology, University of California San Francisco, San Francisco, California
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Edward Siew
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
6Division of Nephrology, Vanderbilt Tennessee Valley Healthcare System, Nashville, Tennessee
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Adriana Hung
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
6Division of Nephrology, Vanderbilt Tennessee Valley Healthcare System, Nashville, Tennessee
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Nisha Bansal
6Division of Nephrology, Vanderbilt Tennessee Valley Healthcare System, Nashville, Tennessee
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Ian de Boer
7Division of Nephrology, University of Washington, Seattle, Washington
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Bryan Kestenbaum
7Division of Nephrology, University of Washington, Seattle, Washington
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Nancy J. Cox
8Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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T. Alp Ikizler
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
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Quinn Wells
3Division of Cardiovascular Medicine, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
8Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Cassianne Robinson-Cohen
1Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee
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Abstract

Background and objectives Elevated fibroblast growth factor-23 (FGF23) has been consistently associated with heart failure, particularly heart failure with preserved ejection fraction, among patients with CKD and in the general population. FGF23 may directly induce cardiac remodeling and heart failure. However, biases affecting observational studies impede robust causal inferences. Mendelian randomization leverages genetic determinants of a risk factor to examine causality. We performed a two-sample Mendelian randomization to assess causal associations between FGF23 and heart failure.

Design, setting, participants, & measurements Genetic instruments were genome-wide significant genetic variants associated with FGF23, including variants near PIP5K1B, RGS14, LINC01229, and CYP24A1. We analyzed data from the Heart Failure Molecular Epidemiology for Therapeutic Targets and BioVU biobanks to examine associations of the four variants with overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced and mid-range ejection fraction. We developed an eGFR polygenic risk score using summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) genome-wide association study of eGFR in >1 million individuals and performed stratified analyses across eGFR polygenic risk score strata.

Results Genetically determined FGF23 was not associated with overall heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium (odds ratio, 1.13; 95% confidence interval, 0.89 to 1.42 per unit higher genetically predicted log FGF23) and the full BioVU sample (odds ratio, 1.32; 95% confidence interval, 0.95 to 1.84). In stratified analyses in BioVU, higher FGF23 was associated with overall heart failure (odds ratio, 3.09; 95% confidence interval, 1.38 to 6.91) among individuals with low eGFR-polygenic risk score (<1 SD below the mean), but not those with high eGFR-polygenic risk score (P interaction = 0.02). Higher FGF23 was also associated with heart failure with preserved ejection fraction among all BioVU participants (odds ratio, 1.47; 95% confidence interval, 1.01 to 2.14) and individuals with low eGFR-polygenic risk score (odds ratio, 7.20; 95% confidence interval, 2.80 to 18.49), but not those high eGFR-polygenic risk score (P interaction = 2.25 × 10−4). No significant associations were observed with heart failure with reduced and midrange ejection fraction.

Conclusion We found no association between genetically predicted FGF23 and heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium. In BioVU, genetically elevated FGF23 was associated with higher heart failure risk, specifically heart failure with preserved ejection fraction, particularly among individuals with low genetically predicted eGFR.

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  • mineral metabolism
  • human genetics
  • heart failure
  • FGF23
  • Mendelian randomization analysis
  • Received January 22, 2022.
  • Accepted May 31, 2022.
  • Copyright © 2022 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 17 (8)
Clinical Journal of the American Society of Nephrology
Vol. 17, Issue 8
August 2022
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Association of Genetically Predicted Fibroblast Growth Factor-23 with Heart Failure
Elvis Akwo, Mindy M. Pike, Lale A. Ertuglu, Nicholas Vartanian, Eric Farber-Eger, Loren Lipworth, Farzana Perwad, Edward Siew, Adriana Hung, Nisha Bansal, Ian de Boer, Bryan Kestenbaum, Nancy J. Cox, T. Alp Ikizler, Quinn Wells, Cassianne Robinson-Cohen
CJASN Aug 2022, 17 (8) 1183-1193; DOI: 10.2215/CJN.00960122

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Association of Genetically Predicted Fibroblast Growth Factor-23 with Heart Failure
Elvis Akwo, Mindy M. Pike, Lale A. Ertuglu, Nicholas Vartanian, Eric Farber-Eger, Loren Lipworth, Farzana Perwad, Edward Siew, Adriana Hung, Nisha Bansal, Ian de Boer, Bryan Kestenbaum, Nancy J. Cox, T. Alp Ikizler, Quinn Wells, Cassianne Robinson-Cohen
CJASN Aug 2022, 17 (8) 1183-1193; DOI: 10.2215/CJN.00960122
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Keywords

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  • FGF23
  • Mendelian randomization analysis

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