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PubMed2025

Network Interactions of Circulating FGF23, HRG-HMGB1, and Cardiac Disease in CKD.

KEY POINTS: Multitrait analysis of genome-wide association study boosts the statistical power to identify novel genetic traits for fibroblast growth factor 23. A functional genomics approach aided network discovery to identify histidine-rich glycoprotein (HRG) and high-mobility group protein box 1 (HMGB1) as key regulators of cardiac disease in CKD. Integration of clinical and genetic data enhances the discovery power and is crucial for understanding the genetic underpinnings of mineral bone disorder related to CKD. BACKGROUND: Genome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism markers but have exclusively focused on single-trait analysis. In this study, we performed a multitrait analysis of GWAS (MTAG) of mineral metabolism, exploring overlapping genetic architecture between traits to identify novel genetic associations for fibroblast growth factor 23 (FGF23). METHODS: We applied MTAG to variants common to GWAS of five genetically correlated mineral metabolism markers in participants of European ancestry. We integrated UK Biobank GWAS for blood levels for phosphate, 25-hydroxyvitamin D, and calcium (n=366,484) and Cohorts for Heart and Aging Research in Genetic Epidemiology GWAS for parathyroid hormone (n=29,155) and FGF23 (n=13,716). We then used supervised and unsupervised deep machine learning to identify novel associations between genetic traits and FGF23. RESULTS: MTAG increased the effective sample size for mineral metabolism markers to n=50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant single-nucleotide polymorphisms for all traits, including 62 loci for FGF23. Many of these loci have not been previously reported in single-trait analyses. Through a functional genomics approach, we identified histidine-rich glycoprotein (HRG) and high-mobility group box 1 (HMGB1) as master regulators of downstream canonical pathways associated with circulating FGF23, and both genes were highly enriched in hypertrophied cardiac tissue of deceased hemodialysis patients. In addition, we found that DNMT3A was associated with uremic toxin, 8-hydroxy-2-deoxyguanosine, a biomarker of DNA damage. In silico gene perturbation analysis revealed that DNMT3A is protective in patients with heart failure caused by hypertrophied or dilated cardiomyopathy. CONCLUSIONS: Our findings highlight the importance of MTAG analysis of mineral metabolism markers to boost the number of genome-wide significant loci for FGF23 to identify novel genetic traits. Functional genomics revealed novel networks that inform unique cellular functions and identified HRG and HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD.

bones, stones, and mineral metabolism↗

PubMed2026

Hemophagocytic Lymphohistiocytosis and Fibroblast Growth Factor 23 (FGF23)-Induced Hypophosphatemia.

Hypophosphatemia is a frequent complication of chimeric antigen receptor T-cell therapy. In this setting, hypophosphatemia has been previously associated with cytokine release syndrome. The mechanisms underlying this electrolyte derangement are not fully understood. Extracellular phosphate consumption by chimeric antigen receptor T cells was demonstrated in vitro, but inflammation is also thought to play a contributing role. We present a case of severe, refractory hypophosphatemia with renal phosphate wasting triggered by hemophagocytic lymphohistiocytosis in acute lymphoblastic leukemia. The diagnosis of phosphate wasting was made at the onset of leukemia and a clinical exacerbation occurred after chimeric antigen receptor T-cell therapy. Diagnostic workup revealed very high fibroblast growth factor 23 (FGF23) levels in the absence of recognized acquired or genetic causes of impaired FGF23 cleavage. This case suggests that inflammation associated with hemophagocytic lymphohistiocytosis may induce FGF23 as a potential mechanism for hypophosphatemia. In this context, we recommend evaluation of renal phosphate wasting and subsequently FGF23 in patients with persistent hypophosphatemia despite standard supplementation.

Humans↗

PubMed2026

Fibroblast Growth Factor 23 as a Prognostic Biomarker in Post-Myocardial Infarction Outcomes: Influence of Renal Function and Its Modulation by Klotho.

BACKGROUND: Elevation of FGF23 (fibroblast growth factor 23) and decreased Klotho levels have been associated with various cardiovascular and renal diseases. However, the combined study of the FGF23-Klotho axis in ischemic heart disease remains elusive. METHODS: We analyzed the associations between circulating FGF23 and Klotho levels with cardiac and renal parameters, as well as mortality outcomes following myocardial infarction (MI). Cardiac tissue from patients with ischemic heart disease and a post-MI mouse model were analyzed to assess myocardial FGF23 expression. Proteomic analysis was performed to examine myocardial pathways activated by FGF23 and regulated by Klotho. RESULTS: We observed an inverse correlation between circulating levels of FGF23 and Klotho in patients after MI. Elevated plasma FGF23 levels were particularly associated with ST-segment-elevation MI and cardiac dysfunction, including reduced left ventricular ejection fraction, prolonged corrected interval, and higher Killip-Kimball classification of cardiac risk, identifying FGF23 as a potential prognostic marker of overall and cardiac-related mortality. In contrast, systemic Klotho levels were reduced in patients with ST-segment-elevation MI but did not correlate with mortality. In cardiac tissue, ischemic injury significantly upregulated FGF23 expression. Although Klotho prevented FGF23-induced proteomic alterations, it did not inhibit cardiac FGF23 overexpression in the post-MI model. CONCLUSIONS: FGF23 represents a promising biomarker for mortality and cardiac dysfunction in patients with MI. Although Klotho does not appear to be a reliable predictor of mortality after MI, its cardioprotective properties suggest a role in modulating FGF23-driven metabolic, structural, and proliferative processes in the myocardium.

Fibroblast Growth Factor-23↗

PubMed2026

Diagnostic and prognostic value of fibroblast growth factor 23 in acute kidney injury: systematic review and meta-analysis.

Background: Acute kidney injury (AKI) is associated with high mortality and adverse outcomes. Fibroblast growth factor 23 (FGF23) has emerged as a potential biomarker for AKI; however, its diagnostic and prognostic utility remains inconsistent.Methods: We conducted a systematic review and meta-analysis of studies evaluating circulating intact FGF23 (iFGF23) or C-terminal FGF23 (cFGF23) (PROSPERO: CRD42022302659). PubMed, EMBASE, CNKI, and Wanfang databases were searched through June 9, 2026. QUADAS-2 was used for quality assessment. A random-effects bivariate model pooled sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (SROC AUC).Results: Twenty-three studies were included: 17 diagnostic, 6 prognostic (one addressing both). For AKI diagnosis, the pooled sensitivity was 0.79 (95% CI 0.73-0.86), specificity 0.82 (95% CI 0.75-0.89), PLR 4.40 (95% CI 2.59-6.21), NLR 0.25 (95% CI 0.16-0.34), DOR 17.49 (95% CI 8.67-35.16), and SROC AUC 0.87 (95% CI 0.81-0.92). Substantial heterogeneity was observed (I2 = 67%), with iFGF23 demonstrating higher accuracy than cFGF23 (AUC 0.91 vs 0.81). For AKI mortality, pooled sensitivity was 0.77 (95% CI 0.69-0.84), specificity 0.76 (95% CI 0.70-0.82), DOR 10.89 (95% CI 6.86-17.30), and SROC AUC 0.77 (95% CI 0.70-0.83). Significant heterogeneity was noted (I2 = 86.2% for sensitivity, 80.4% for specificity). No significant publication bias was detected.Conclusions: Circulating FGF23 exhibits moderate-to-high diagnostic and moderate prognostic performance in AKI, though interpretation is limited by substantial heterogeneity. It may serve as a complementary biomarker for risk stratification, pending further validation with standardized protocols.

Humans↗

PubMed2025

Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.

AIMS: Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes. MATERIALS AND METHODS: Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies. RESULTS: Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy. CONCLUSIONS: This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.

Humans↗

PubMed2025

Shared and divergent acute cardiovascular risk protein responses to lipid infusion in women with and without PCOS.

AIMS: Elevated circulating lipids are linked to cardiovascular disease (CVD), especially in insulin-resistant states like polycystic ovary syndrome (PCOS), but their effects on cardiovascular risk proteins (CVRPs) remain unclear. This study used a two-step approach to examine acute cardiovascular proteomic responses to lipid-induced metabolic stress. We first identified proteins altered by lipids and insulin in healthy control (HC) women, then assessed whether these responses were similar or divergent in women with PCOS. METHODS: In a randomised cross-over study, 10 healthy controls and 12 women with PCOS underwent 5-h saline (control) or intralipid infusions. After 3 h, a 2-h hyperinsulinemic-euglycemic clamp was initiated. Plasma CVRP expression was assessed at baseline, post-lipid (180 min) and post-clamp (300 min) using SOMAscan proteomics. STRING and pathway enrichment analyses were performed to explore functional associations. RESULTS: In the HC group, lipid infusion altered the expression of 11 out of 54 CVRPs including increases in RANK, IL2RA, TACI, SLAF5 and DCN (p <0.05) and decreases in THPO, BOC, SOD2, FGF23, and AgRP (p <0.05). Most changes reversed with insulin, but BOC, SOD2, MMP12, FGF23, and DCN remained dysregulated. In PCOS, responses mirrored the HC group except for lower AgRP following lipid infusion (p <0.01), and persistent elevation of SLAF5 and DCN following insulin (p <0.05). Enrichment analysis linked altered proteins to immune activation, cell proliferation, and cytokine-receptor signalling. CONCLUSION: Acute lipid infusion revealed shared and phenotype-specific proteomic responses linked to early vascular stress. In PCOS, persistent dysregulation suggests reduced metabolic adaptability, with exploratory signals that may complement established biomarkers of early cardiovascular risk.

Humans↗

PubMed2025

CAUSAL ASSOCIATION BETWEEN SEPSIS AND FIBROBLAST GROWTH FACTORS AS WELL AS THEIR RECEPTORS LEVELS: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY.

Objective: The potential association between sepsis risk and circulating levels of fibroblast growth factors (FGFs) and their receptors (FGFRs) has been a focus of research; however, the causal relationship between them remains to be elucidated. We hypothesize a causal association between genetically predicted FGFs, FGFRs, and sepsis risk, and we conduct a Mendelian randomization (MR) study to validate this hypothesis. Methods: We utilized a two-sample MR design to assess the effect of genetic variants associated with various FGFs (FGF1, FGF2, FGF7, FGF16, FGF19, FGF21, FGF23, FGF5) and FGFRs (FGFR1, FGFR2, FGFR3, α-Klotho) on sepsis risk, using genome-wide association study summary statistics. Our MR analyses employed the inverse-variance weighted (IVW) method, along with weighted median, weighted mode, and MR-Egger regression, supplemented by sensitivity analyses to ensure robustness. Results: The MR analysis identified an unequal number of instrumental variables ranging from 2 to 17 for FGFs and FGFRs when sepsis was the outcome. No significant correlation was found between genetically determined FGF levels and sepsis risk by IVW analysis (all P > 0.05). Correspondingly, similar nonsignificant associations were observed for FGFRs (all P > 0.05). Other MR methods corroborated the IVW findings. Sensitivity analyses, including Cochran's Q test, MR-Egger, and MR pleiotropy residual sum and outlier, indicated no significant heterogeneity or pleiotropy in the relationships, with the exception of a nonsignificant correlation between FGFR1 and sepsis that persisted after the exclusion of an outlier (odds ratio, 0.84; P = 0.34). Conclusion: The analysis found no significant causal associations between FGFs, their receptors, and sepsis risk, indicating a need for further research on their complex interactions.

Humans↗