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Klotho polymorphisms, FGF23 and mortality among elderly men (Swedish MrOs).
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Wallenberg Laboratory for Cardiovascular Research, University of Göteborg, Göteborg, Sweden.
Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences and Orthopedic Surgery, Lund University, Skåne University Hospital, Sweden..
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(English)Manuscript (preprint) (Other academic)
Abstract [en]


Westerberg, P-A and Kindmark, A contributed equally in preparation of the manuscript.

Introduction. α-Klotho is the co receptor for Fibroblast growth factor(FGF)23and crucial for phosphate and vitamin D metabolism. Variants in the KLOTHO (KL) gene are associated with longevity and cardiovascular morbidities. Primary aim of this study is to examine if variations in  KL affect mortality risk in a cohort of elderly men. Secondary aims are to examine associations with serum levels of FGF23, phosphate and renal function.

Methods and results. 27 single nucleotide polymorphisms (SNP) in KLOTHO were genotyped using single base primer extension mass array technique on samples from 2924 men, aged 69 to 81 years, included in Swedish MrOs. After in average 6.1 years of follow up 584 had died, 214 of cardiovascular cause.  After quality analyses and tagging of haplotypes 11 SNPs were analyzed for variation in  mortality risk, serum levels of FGF23, phosphate, calcium and renal function. There were no associations with mortality of all cause. One SNP, (rs398655), in proximity to the promoter, demonstrated an increased Hazard ratio (95% Confidence interval(CI)) of 53% (95% CI, 8-118%) for death due to CVD in heterozygotes compared to homozygotes. Analysis using a dominant model showed an association between SNPs in the 5’ end of the gene and eGFR, phosphate level and logFGF23 (P=0.01).

Conclusion. KL polymorphisms are associated with variation in FGF23 and phosphate.

Keyword [en]
Klotho, FGF23, mineral metabolism, phosphatonin, mortality, elderly
National Category
Other Basic Medicine
URN: urn:nbn:se:uu:diva-188225OAI: oai:DiVA.org:uu-188225DiVA: diva2:576846
Available from: 2012-12-14 Created: 2012-12-14 Last updated: 2013-02-11
In thesis
1. Aspects of Fibroblast Growth Factor 23 in Mild to Moderate Renal Dysfunction
Open this publication in new window or tab >>Aspects of Fibroblast Growth Factor 23 in Mild to Moderate Renal Dysfunction
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Disturbances in mineral metabolism contribute to vascular calcification and mortality risk in chronic kidney disease (CKD). Serum levels of fibroblast growth factor (FGF)23, a bone derived, phosphaturic peptide, are associated with cardiovascular mortality in CKD. Membrane bound klotho(KL) is an obligate co receptor for FGF23 signaling in the kidney. To study aspects of FGF23 in mild to moderate impairment of renal function we have analyzed FGF23, estimated glomerular filtration rate (eGFR), parathyroid hormone(PTH), 1,25 (OH)2 vitamin D (1,25D), calcium and phosphate in one patient with a FGF23 producing tumor, before and after tumor removal (study 1), in 72 CKD patients with varying degree of renal dysfunction (study 2), in 9 healthy kidney donors, before and after nephrectomy (study 3). We also analyzed FGF23 (study 4), and performed genotyping of 27 single nucleotide polymorphisms (SNP) of the KL gene (study 5) in 2838 elderly Swedish men (MrOs study) and examined the association with mortality.

FGF23 normalizes in 30-45 minutes after removal of a FGF23 producing tumor (study 1). 1,25D increases in hours and remains elevated months, even when the other parameters have normalized. FGF23 increase early in CKD, initially slowly, in correlation with PTH, but exponentially when hyperphosphatemia ensues (study 2). After unilateral nephrectomy (study 3) mineral homeostasis remain stable, initially due to a rise in PTH and later to an increase in FGF23.

FGF23 levels are not correlated with mortality in elderly men after adjustment for eGFR, but with mortality due to cardiovascular disease, even in persons with normal eGFR (study 4). Polymorphism of the KL gene do not correlate with increased mortality risk in elderly men (study 5), but there is a modulating effect on FGF23 levels.

FGF23 is of importance in maintaining phosphate homeostasis as renal function declines. It is co regulated with PTH until advanced renal dysfunction, and adjust the 1,25D to the actual GFR. FGF23 is associated with cardiovascular mortality. Further studies are needed to determine the mechanism, and if reduction of FGF23 by reducing phosphate intake may be beneficial even in persons with mild to moderate renal function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 852
FGF23, phosphate, mineral metabolism, elderly, mortality
National Category
Urology and Nephrology
Research subject
urn:nbn:se:uu:diva-188233 (URN)978-91-554-8564-1 (ISBN)
Public defence
2013-02-08, Enghoffsalen, Akademiska Sjukhuset , ingång 50, plan1, Uppsala, 13:00 (English)
Available from: 2013-01-17 Created: 2012-12-14 Last updated: 2013-04-02Bibliographically approved

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