FGF23 is associated with risk of intracerebral hemorrhage
Intracerebral hemorrhage (ICH) is caused by bleeding within the brain. Very few circulating biomarkers are known to be associated with the risk of ICH. Fibroblast growth factor 23 (FGF23) is a bone-derived protein hormone associated with mortality in patients with heart failure. A recent nested case–control study showed that FGF23 is associated with risk of intracerebral hemorrhage: Fibroblast growth factor 23 is associated with risk of intracerebral hemorrhage. Svensson EH, Söderholm M. Eur J Neurol. 2022 Jan;29(1):114-120. doi: 10.1111/ene.15060. PMID: 34379844.
Background and purpose: Fibroblast growth factor 23 (FGF23) is an osteogenic hormone associated with chronic kidney disease and is an emerging risk factor for several cardiovascular diseases. The association of FGF23 with stroke is unclear. The aim of this study was to investigate the association of FGF23 with incident intracerebral hemorrhage (ICH).
Methods: This was a nested case-control study of 220 ICH cases and 244 age- and sex-matched controls from the population-based Malmö Diet and Cancer Study (n = 28,449). Incident ICH cases were ascertained using national registers and classified by bleeding location. Logistic regression was used to study the association of plasma levels of FGF23 with incident ICH, adjusting for potential ICH risk factors. Subgroup analyses were performed for lobar and non-lobar ICH, fatal ICH, ICH with large volume and ICH with poor functional outcome, respectively.
Results: Higher FGF23 levels at baseline were significantly associated with incident ICH. After multivariable adjustment, the odds ratio for the association with all ICH was 1.84 (95% confidence interval [CI] 1.25-2.71, p = 0.002) per doubling of FGF23 concentration. For lobar and non-lobar ICH, odds ratios were 1.73 (95% CI 1.04-2.87, p = 0.035) and 2.13 (95% CI 1.32-3.45, p = 0.002), respectively. FGF23 was also significantly associated with fatal ICH, ICH with large volume and ICH with poor functional outcome.
Conclusions: Higher FGF23 was associated with incident ICH in this nested case-control study. Further studies are required to explore whether the association is causal.
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Wright CB, Dong C, Stark M, Silverberg S, Rundek T, Elkind MS, Sacco RL, Mendez A, Wolf M. Neurology 2014. 13;82(19):1700-6. PMID: 24706015.
Objective: To examine fibroblast growth factor 23 (FGF23) as a risk factor for incident stroke in a racially/ethnically diverse population-based urban cohort.
Methods: Stroke-free Northern Manhattan Study participants with FGF23 measurements (n = 2,525) were followed for a mean of 12 (±5) years to detect incident strokes. We used Cox proportional hazards models to estimate the association of baseline FGF23 with incident total, ischemic, and hemorrhagic stroke.
Results: Median FGF23 was 57 relative units (RU)/mL (interquartile range = 44-81 RU/mL). Each unit increase of natural log-transformed FGF23 conferred a 40% greater overall stroke risk after adjusting for estimated glomerular filtration rate and sociodemographic and vascular risk factors (hazard ratio = 1.4, 95% confidence interval 1.1-1.6, p = 0.004). Penalized spline analysis revealed a linear association with overall stroke risk at ≥90 RU/mL FGF23, compared with <90 RU/mL (hazard ratio = 1.5, 95% confidence interval = 1.2-2.1, p = 0.004). Greater FGF23 conferred a doubling of intracerebral hemorrhage (ICH) risk but no significant increased risk of ischemic stroke. The associations of elevated FGF23 levels with greater risks of overall stroke and ICH events were independent of phosphate and parathyroid hormone levels and were similar among participants without chronic kidney disease.
Conclusions: Elevated FGF23 was a risk factor for overall stroke and ICH events, in particular in a racially and ethnically diverse urban community, independent of chronic kidney disease.
Panwar B, Jenny NS, Howard VJ, Wadley VG, Muntner P, Kissela BM, Judd SE, Gutiérrez OM. Stroke. 2015. 46(2):322-8. doi: 10.1161/STROKEAHA.114.007489. PMID: 25563643.
Background and purpose: Fibroblast growth factor 23 (FGF23) is a hormone that regulates phosphorus and vitamin D metabolism. Elevated FGF23 concentrations are associated with excess risk of cardiovascular disease. Associations of FGF23 with stroke outcomes are less clear.
Methods: Using a case-cohort study design, we examined the association of baseline plasma FGF23 concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults aged ≥45 years. FGF23 was measured in 615 participants who developed incident stroke (cases) and in 936 participants randomly selected from the REGARDS cohort (comparison subcohort).
Results: In multivariable-adjusted models, higher calcium and phosphorus concentrations, lower estimated glomerular filtration rate and higher urine albumin excretion were independently associated with higher FGF23. There was no statistically significant association of FGF23 with risk of all-cause stroke in Cox models adjusted for demographic factors and established stroke risk factors (hazard ratio comparing fourth with first quartile 1.19; 95% confidence interval, 0.78-1.82). In prespecified models stratified by stroke subtypes, there was a graded association of FGF23 with risk of cardioembolic stroke in fully adjusted models (quartile 1, reference; quartile 2 hazard ratio, 1.48; 95% confidence interval, 0.63-3.47; quartile 3 hazard ratio, 1.99; 95% confidence interval, 0.89-4.44; quartile 4 hazard ratio, 2.52; 95% confidence interval, 1.08-5.91). There were no statistically significant associations of FGF23 with other ischemic stroke subtypes or with hemorrhagic strokes.
Conclusions: Higher FGF23 concentrations were associated with higher risk of cardioembolic but not with other stroke subtypes in community-dwelling adults. Additional studies should delineate reasons for these findings.