Causal Effect of Fibroblast Growth Factor 23 on Osteoporosis and Cardiometabolic Disorders: A Mendelian Randomization Study

Abstract Pathological excess of fibroblast growth factor 23 (FGF23) causes mineral and bone disorders. However, the causality of FGF23 in the development of osteoporosis remains unknown. Whether FGF23 has systemic effects on cardio-metabolic disorders beyond regulating mineral metabolism is also controversial. In this study, we evaluated the causal effect of FGF23 on osteoporosis and cardiometabolic disorders using Mendelian randomization (MR) analysis. Summary statistics for single-nucleotide polymorphisms with traits of interest were obtained from the relevant genome-wide association studies. As a result, FGF23 was found to be inversely associated with femoral neck-BMD (odds ratio [OR] 0.682, 95% confidence interval [CI] 0.546–0.853, p = 8e-04) and heel estimated BMD (eBMD) (OR 0.898, 95%CI 0.820–0.985, p = 0.022) in the inverse-variance-weighted analysis, but not lumbar spine-BMD and fractures. The results were supported by the weighted-median analysis, and there was no evidence of pleiotropy in the MR-Egger analysis. FGF23 was directly associated with FN-BMD and eBMD after adjustment for estimated glomerular filtration rate, height, and body mass index in multivariable MR analysis. On the other hand, there was no association between FGF23 and cardiometabolic traits including cardio artery disease, brachial-ankle pulse wave velocity, intima-media thickness of carotid arteries, systolic and diastolic blood pressure, fasting glucose, high and low-density lipoprotein cholesterol, and triglycerides. Therefore, FGF23 has been causally associated with bone loss. In contrast, FGF23 has not been causally associated with cardiometabolic disorders. The data of this study provides important insights into the role of FGF23 in the pathogenesis of osteoporosis and cardiometabolic disorders.

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Investigating the causal effect of fibroblast growth factor 23 on osteoporosis and cardiometabolic disorders: A Mendelian randomization study

Bone ◽

10.1016/j.bone.2020.115777 ◽

2021 ◽

Vol 143 ◽

pp. 115777

Author(s):

Maki Yokomoto-Umakoshi ◽

Hironobu Umakoshi ◽

Takashi Miyazawa ◽

Masatoshi Ogata ◽

Ryuichi Sakamoto ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Mendelian Randomization ◽

Causal Effect ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Cardiometabolic Disorders

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Genetically Predicted Fibroblast Growth Factor 23 and Major Cardiovascular Diseases, Their Risk Factors, Kidney Function, and Longevity: A Two-Sample Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.699455 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ying Liang ◽

Shan Luo ◽

C. Mary Schooling ◽

Shiu Lun Au Yeung

Keyword(s):

Risk Factors ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Kidney Function ◽

Mendelian Randomization ◽

Fibroblast Growth Factor 23 ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Fibroblast Growth ◽

Potential Biomarker

IntroductionFibroblast growth factor 23 (FGF23), a potential biomarker for kidney function, is related to cardiovascular disease (CVD) and diabetes, although it is unclear whether the relation is causal. This study evaluated the associations of genetically predicted FGF23 with major CVDs, their risk factors, kidney function, and longevity using Mendelian randomization (MR).MethodsThis is a two-sample MR study using summary statistics from large genome-wide association studies. Primary outcomes included coronary artery disease (CAD), myocardial infarction, heart failure, and atrial fibrillation. Secondary outcomes included cardiovascular risk factors, kidney function, and longevity. We used four single-nucleotide polymorphisms (SNPs) predicting FGF23, excluding rs2769071 in the ABO gene, which likely violates the MR exclusion-restriction assumption. We used inverse-variance weighted (IVW) as the primary statistical method to assess associations of FGF23 with the outcomes. Sensitivity analyses included weighted median (WM) and MR-Egger. We repeated the analyses including all five SNPs. Last, we validated the positive findings from the main analyses in a smaller study, i.e., FinnGen.ResultsUsing IVW, genetically predicted higher FGF23 was inversely associated with risk of CAD [odds ratio (OR): 0.69 per logtransformed FGF23 (pg/ml) increase, 95% confidence interval (CI): 0.52–0.91] and type 2 diabetes mellitus (T2DM) (OR: 0.70, 95% CI: 0.52–0.96), but not with the other outcomes. The WM and MR-Egger estimates were directionally consistent.ConclusionThis study suggests that genetically predicted higher FGF23 may be protective against CAD and T2DM. Future studies should explore the underlying mechanisms related to the potential protective effect of FGF23. FGF23 was unlikely a cause of poorer renal function.

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Faculty Opinions recommendation of Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739006752.793580774 ◽

2020 ◽

Author(s):

Jason Stubbs

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Mineral Metabolism ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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Fibroblast Growth Factor 23, Klotho, and Disordered Mineral Metabolism in Chronic Kidney Disease: Unraveling the Intricate Tapestry of Events and Implications for Therapy

Journal of Renal Nutrition ◽

10.1053/j.jrn.2013.01.024 ◽

2013 ◽

Vol 23 (3) ◽

pp. 250-254 ◽

Cited By ~ 7

Author(s):

Orlando M. Gutiérrez

Keyword(s):

Chronic Kidney Disease ◽

Growth Factor ◽

Kidney Disease ◽

Fibroblast Growth Factor ◽

Mineral Metabolism ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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Serum Level of Fibroblast Growth Factor 23 and its Relationship with Bone Mineral Metabolism in Maintenance Renal Transplant Patients

Transplantation Journal ◽

10.1097/00007890-201211271-01621 ◽

2012 ◽

Vol 94 (10S) ◽

pp. 828

Author(s):

A. Sánchez Fructuoso ◽

M. L. Maestro ◽

I. Perez Flores ◽

R. Valero ◽

S. Rafael ◽

...

Keyword(s):

Growth Factor ◽

Renal Transplant ◽

Serum Level ◽

Fibroblast Growth Factor ◽

Bone Mineral ◽

Mineral Metabolism ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Bone Mineral Metabolism ◽

Transplant Patients

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Fibroblast Growth Factor 23: Mineral Metabolism and Beyond

Current Perspectives in Kidney Diseases - Contributions to Nephrology ◽

10.1159/000468952 ◽

2017 ◽

pp. 83-95 ◽

Cited By ~ 10

Author(s):

Alexander Grabner ◽

Sandro Mazzaferro ◽

Giuseppe Cianciolo ◽

Stefanie Krick ◽

Irene Capelli ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Mineral Metabolism ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans

Journal of Clinical Medicine ◽

10.3390/jcm9082640 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2640

Author(s):

Bernhard Bielesz ◽

Thomas Reiter ◽

Fabian Peter Hammerle ◽

Wolfgang Winnicki ◽

Marija Bojic ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Growth Factor ◽

Kidney Disease ◽

Fibroblast Growth Factor ◽

Iron Metabolism ◽

Mineral Metabolism ◽

Fibroblast Growth Factor 23 ◽

Biologically Active ◽

Mean Corpuscular Hemoglobin ◽

Fibroblast Growth

Anemia in chronic kidney disease (CKD) is an almost universal complication of this condition. Fibroblast growth factor 23 (FGF23), a key-player in mineral metabolism, is reportedly associated with anemia and hemoglobin levels in non-dialysis CKD patients. Here, we sought to further characterize this association while taking into account the biologically active, intact fraction of FGF23, iron metabolism, and erythropoietin (EPO). Hemoglobin, EPO, iron, and mineral metabolism parameters, including both intact and c-terminal-FGF23 (iFGF23 and cFGF23, respectively) were measured cross-sectionally in 225 non-dialysis CKD patients (stage 1–5, median eGFR: 30 mL/min./1.73m2) not on erythropoiesis stimulating agents or intravenous iron therapy. Statistical analysis was performed by multiple linear regression. After adjustment for eGFR and other important confounders, only cFGF23 but not iFGF23 was significantly associated with hemoglobin levels and this association was largely accounted for by iron metabolism parameters. cFGF23 but not iFGF23 was also associated with mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV), again in dependence on iron metabolism parameters. Similarly, EPO concentrations were associated with cFGF23 but not iFGF23, but their contribution to the association of cFGF23 with hemoglobin levels was marginal. In pre-dialysis CKD patients, the observed association of FGF23 with hemoglobin seems to be restricted to cFGF23 and largely explained by the iron status.

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