Majd A.I. Mirza

Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community

OBJECTIVE Subjects with chronic kidney disease (CKD) are at higher risk for cardiovascular (CV) disease than the general population. These patients have elevated circulating levels of FGF23, which predict for increased mortality in CKD patients on hemodialysis. Since CV disease is a major cause of death in CKD, we investigated the association between FGF23 and vascular function. METHODS AND RESULTS We employed a community-based cohort of subjects aged 70, the PIVUS study (n=967), to investigate the relation between serum FGF23, endothelium function and arterial stiffness. Higher FGF23 was weakly associated with both impaired endothelium-dependent (beta=-0.08, p<0.05) and endothelium-independent (beta=-0.08, p<0.01) vasodilation. The association was stronger in subjects with eGFR> or =90mL/min/1.73m(2) (beta=-0.19 and beta=-0.22, respectively, p<0.001). In addition, higher FGF23 was associated with increased arterial stiffness exclusively in subjects with an age-adjusted impaired renal function (eGFR<60mL/min/1.73m(2)) (beta=0.26, p<0.001). All associations were independent of gender, biochemical covariates and established CV risk factors. CONCLUSIONS Higher serum FGF23 levels, even within the normal range, are independently associated with impaired vasoreactivity and increased arterial stiffness in the community. Additional studies are required to determine possible direct vascular effects of FGF23 and whether FGF23 is a modifiable CV risk factor.

Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population ☆

Fibroblast growth factor-23 (FGF23) is a hormonal regulator of circulating phosphate and vitamin D levels. Serum FGF23 is elevated in chronic kidney disease (CKD) and is a prognostic marker of poor outcomes, such as faster CKD progression and increased mortality in hemodialysis patients. Despite the high prevalence of cardiovascular disease in CKD, the relation between circulating FGF23 and cardiovascular risk factors, both in CKD and in the community, has not been studied in detail. We evaluated the relation between FGF23, left ventricular mass index (LVMI), hypertrophy (LVH) and LV geometry, employing the community-based PIVUS cohort. In total, 795 Swedish men and women aged 70 were included of which 164 had an age-adjusted diminished renal function (estimated glomerular filtration rate<60mL/min/1.73m(2)). FGF23 was positively associated with LVMI (beta=0.11, CI 0.01-0.18), with increased odds for the presence of LVH (OR 1.28, CI 1.09-1.51) and for concentric hypertrophy (OR 1.45, CI 1.19-1.77) in the whole population. All associations were stronger in subjects with eGFR<60mL/min/1.73m(2) (beta=0.30, CI 0.15-0.46 for LVMI; OR 1.86, CI 1.30-2.67 for the presence of LVH; OR 1.83, CI 1.17-2.85 and OR 1.87, CI 1.08-3.22 for concentric and eccentric hypertrophy, respectively). The results were essentially unaltered in multivariate models. In summary, elevated serum FGF23 levels, even within the normal range, are associated with increased LVMI and increased risk for the presence of LVH in elderly subjects. Additional longitudinal studies that evaluate the predictive power of FGF23 and whether FGF23 has additional clinical applications are needed.

Relationship between circulating FGF23 and total body atherosclerosis in the community

BACKGROUND Fibroblast growth factor-23 (FGF23) is a regulator of mineral metabolism and has been suggested to play a role in vascular calcification in chronic kidney disease (CKD). Data on the association between FGF23 and atherosclerosis, both in CKD and in the community, is limited. METHODS The total body atherosclerosis score (AS) was determined by a magnetic resonance imaging-based angiography in 306 elderly men and women, representing a subsample of the community-based PIVUS cohort. Subjects were divided into three categories based on AS: AS = 0, low AS and high AS. Serum FGF23 was measured using a two-site monoclonal antibody ELISA. RESULTS In continuous and multi-category regression models, higher FGF23 was associated with a significant increase in the odds of having a high AS (OR 1.43, CI 1.06-1.92 to OR 3.01, CI 1.52-5.99). This association was stronger in individuals with eGFR <60 mL/min/1.73 m(2) (n = 27), reaching a nearly 6-fold increase in the odds for a high AS in the upper FGF23 tertile (OR 5.64, CI 2.78-11.5). We found weaker support for a relationship between FGF23 and the presence of atherosclerosis as subjects in the highest FGF23 tertile had an increased risk for an AS > 0 in crude models (OR 1.93, CI 1.05-3.55), but this was not statistically significant in adjusted (OR 1.42, CI 0.74-1.72) models. CONCLUSIONS We provide novel evidence supporting an association between serum FGF23 and total body atherosclerosis in the community. Additional studies are warranted to determine the prospective relationship between FGF23 and atherosclerosis, and whether FGF23 is a modifiable cardiovascular risk factor.

Circulating Fibroblast Growth Factor-23 Is Associated With Fat Mass and Dyslipidemia in Two Independent Cohorts of Elderly Individuals

Objective—Disturbances in mineral metabolism define an increased cardiovascular risk in patients with chronic kidney disease. Fibroblast growth factor-23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and has recently been implicated as a putative pathogenic factor in cardiovascular disease. Because other members of the FGF family play a role in lipid and glucose metabolism, we hypothesized that FGF23 would associate with metabolic factors that predispose to an increased cardiovascular risk. The goal of this study was to investigate the relationship between FGF23 and metabolic cardiovascular risk factors in the community. Methods and Results—Relationships between serum FGF23 and body mass index (BMI), waist circumference, waist-to-hip ratio, serum lipids, and fat mass were examined in 2 community-based, cross-sectional cohorts of elderly whites (Osteoporotic Fractures in Men Study: 964 men aged 75±3.2; Prospective Investigation of the Vasculature in Uppsala Seniors study: 946 men and women aged 70). In both cohorts, FGF23 associated negatively with high-density lipoprotein and apolipoprotein A1 (7% to 21% decrease per 1-SD increase in log FGF23; P<0.01) and positively with triglycerides (11% to 14% per 1-SD increase in log FGF23; P<0.01). A 1-SD increase in log FGF23 was associated with a 7% to 20% increase in BMI, waist circumference, and waist-to-hip ratio and a 7% to 18% increase in trunk and total body fat mass (P<0.01) as determined by whole-body dual x-ray absorptiometry. FGF23 levels were higher in subjects with the metabolic syndrome compared with those without (46.4 versus 41.2 pg/mL; P<0.05) and associated with an increased risk of having the metabolic syndrome (OR per 1-SD increase in log FGF23, 1.21; 95% CI, 1.04 to 1.40; P<0.05). Conclusion—We report for the first time on associations between circulating FGF23, fat mass, and adverse lipid metabolism resembling the metabolic syndrome, potentially representing a novel pathway(s) linking high FGF23 to an increased cardiovascular risk.

Serum Fibroblast Growth Factor-23 (FGF-23) and Fracture Risk in Elderly Men

A normal mineral metabolism is integral for skeletal development and preservation of bone integrity. Fibroblast growth factor 23 (FGF‐23) is a bone‐derived circulating factor that decreases serum concentrations of inorganic phosphorous (Pi) and 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3]. Increased FGF‐23 expression is a direct or indirect culprit in several skeletal disorders; however, the relation between FGF‐23 and fracture risk remains undetermined. We evaluated the prospective relation between serum intact FGF‐23 (measured by a two‐site monoclonal antibody ELISA) and fracture risk employing the Swedish part of the population‐based Osteoporotic Fractures in Men Study (MrOS; n = 2868; mean age 75.4 ± 3.2 years; median follow‐up period 3.35 years). The incidence of at least one validated fracture after baseline was 20.4 per 1000 person‐years. FGF‐23 was directly related to the overall fracture risk [age‐adjusted hazard ratio (HR) per SD increase = 1.20, 95% confidence interval (CI) 1.03–1.40] and vertebral fracture risk (HR = 1.33, 95% CI 1.02–1.75). Spline models revealed a nonlinear relation between FGF‐23 and fracture risk, with the strongest relation at FGF‐23 levels above 55.7 pg/mL. FGF‐23 levels above 55.7 pg/mL also were associated with an increased risk for hip and nonvertebral fractures (HR = 2.30, 95% CI 1.16–4.58, and HR = 1.63, 95% CI 1.01–2.63, respectively). These relations remained essentially unaltered after adjustment for bodymass index (BMI), bone mineral density (BMD), glomerular filtration rate, 25(OH)2D3, parathyroid hormone (PTH), and other fracture risk factors. In conclusion, FGF‐23 is a novel predictor of fracture risk in elderly men.

Critical evaluation of the FANTOM3 non-coding RNA transcripts

We studied the genomic positions of 38,129 putative ncRNAs from the RIKEN dataset in relation to protein-coding genes. We found that the dataset has 41% sense, 6% antisense, 24% intronic and 29% intergenic transcripts. Interestingly, 17,678 (47%) of the FANTOM3 transcripts were found to potentially be internally primed from longer transcripts. The highest fraction of these transcripts was found among the intronic transcripts and as many as 77% or 6929 intronic transcripts were both internally primed and unspliced. We defined a filtered subset of 8535 transcripts that did not overlap with protein-coding genes, did not contain ORFs longer than 100 residues and were not internally primed. This dataset contains 53% of the FANTOM3 transcripts associated to known ncRNA in RNAdb and expands previous similar efforts with 6523 novel transcripts. This bioinformatic filtering of the FANTOM3 non-coding dataset has generated a lead dataset of transcripts without signs of being artefacts, providing a suitable dataset for investigation with hybridization-based techniques.