title: FGF23 gene variation and its association with phosphate homeostasis and bone mineral density in Finnish children and adolescents.
abstract: Fibroblast growth factor 23 (FGF23), a bone-derived hormone, participates in the hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25-dihydroxyvitamin D, plasma phosphate (Pi), and diet. Inappropriately high serum FGF23, seen in certain genetic and acquired disorders, results in urinary phosphate wasting and impaired bone mineralization. This study investigated the impact of FGF23 gene variation on phosphate homeostasis and bone health. The study included 183 children and adolescents (110 girls) aged 7-19 years (median 13.2years). Urine and blood parameters of calcium and phosphate homeostasis were analyzed. Bone characteristics were quantified by DXA and peripheral quantitative computed tomography (pQCT). Genetic FGF23 variation was assessed by direct sequencing of coding exons and flanking intronic regions. Nine FGF23 polymorphisms were detected; three of them were common: rs3832879 (c.212-37insC), rs7955866 (c.716C>T, p.T239M) and rs11063112 (c.2185A>T). Four different haplotypes and six different diplotypes were observed among these three polymorphisms. The variations in FGF23 significantly associated with plasma PTH and urinary Pi excretion, even after adjusting for relevant covariates. FGF23 variations independently associated with total hip BMD Z-score, but not with other bone outcomes. In instrument analysis, genetic variance in FGF23 was considered a weak instrument as it only induced small variations in circulating FGF23, PTH and Pi concentrations (F statistic less than 10). The observed associations between FGF23 variations and circulating PTH, and Pi excretion and total hip BMD Z-scores suggest that FGF23 polymorphisms may play a role in mineral homeostasis and bone metabolism.
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland. Electronic address: minna.pekkinen@helsinki.fi.
authors.forename: Minna
authors.initials: M
authors.lastname: Pekkinen
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland; Department of Endocrinology, Sahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, Sweden.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Laine
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Mäkitie
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Eira
authors.initials: E
authors.lastname: Leinonen
authors.affiliation: Calcium Research Unit, Department of Food and Environmental Sciences (Nutrition), University of Helsinki, Helsinki, Finland.
authors.forename: Christel
authors.initials: C
authors.lastname: Lamberg-Allardt
authors.affiliation: Department of Pediatrics, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Viljakainen
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland; Department of Pediatrics, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000000981:diagnostic imaging; D002648:Child; D003720:Densitometry; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000235:genetics*; D005387:Finland; D056726:Genetic Association Studies; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D016014:Linear Models; D008297:Male; D010710:Phosphates / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017434:Protein Structure, Tertiary; D014057:Tomography, X-Ray Computed
chemical_list: C000717427:FGF23 protein, human; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: Adolescent; Bone morphometry; Child; FGF23; PTH; Phosphate