Variation in the fibroblast growth factor 23 (FGF23) gene associates with serum FGF23 and bone strength in infants

Maria Enlund-Cerullo; Elisa Holmlund-Suila; Saara Valkama; Helena Hauta-Alus; Jenni Rosendahl; Sture Andersson; Minna Pekkinen; Outi Mäkitie

doi:10.3389/fgene.2023.1192368

Variation in the fibroblast growth factor 23 (FGF23) gene associates with serum FGF23 and bone strength in infants

Front Genet. 2023 May 22:14:1192368. doi: 10.3389/fgene.2023.1192368. eCollection 2023.

Authors

Maria Enlund-Cerullo^{1

2

3}, Elisa Holmlund-Suila^{1

3}, Saara Valkama^{1

3}, Helena Hauta-Alus^{1

3

4

5}, Jenni Rosendahl^{1

3}, Sture Andersson¹, Minna Pekkinen^{1

2

3}, Outi Mäkitie^{1

2

3

6}

Affiliations

¹ Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
² Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.
³ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴ Public Health Research, National Institute for Health and Welfare (THL), Helsinki, Finland.
⁵ PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
⁶ Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Introduction: The effects of genetic variation in fibroblast growth factor 23 (FGF23) are unclear. This study explores the associations of single-nucleotide polymorphisms (SNPs) of FGF23 with phosphate and vitamin D metabolism and bone strength in early childhood. Methods: The study is part of the vitamin D intervention in infant (VIDI) trial (2013-2016), in which healthy term infants born to mothers of Northern European origin received vitamin D₃ supplementation of 10 or 30 μg/day from 2 weeks to 24 months of age (ClinicalTrials.gov NCT01723852). Intact and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), parathyroid hormone, phosphate, and peripheral quantitative computed tomography (pQCT)-derived bone strength parameters were analyzed at 12 and 24 months. The study included 622 VIDI participants with genotyping data on FGF23 SNPs rs7955866, rs11063112, and rs13312770. Results: Rs7955866 minor allele homozygotes had lowest cFGF23 at both time-points (mixed model for repeated measurements, p_variant = 0.009). Minor alleles of rs11063112 were associated with a greater age-related decrease in phosphate concentration (p_interaction = 0.038) from 12 to 24 months. Heterozygotes of rs13312770 had the greatest total bone mineral content (total BMC), cross-sectional area (total CSA), and polar moment of inertia (PMI) at 24 months (ANOVA p = 0.005, 0.037, and 0.036, respectively). Rs13312770 minor alleles were associated with a greater increase of total BMC, but a smaller increase of total CSA and PMI, during follow-up (p_interaction <0.001, 0.043, and 0.012, respectively). Genotype of FGF23 did not modify 25-OHD. Conclusion: The study finds that genetic variation in FGF23 modifies cFGF23, phosphate, and pQCT-derived bone strength parameters from 12 to 24 months of age. These findings potentially promote an understanding of the regulation of FGF23 and its role in bone metabolism and temporal changes thereof during early childhood.

Keywords: FGF23; bone strength; genetic variation; infants (0–24 months); vitamin D.

Associated data

ClinicalTrials.gov/NCT01723852

Grants and funding

The study was supported by grants from the Folkhälsan Research Foundation, the Finnish Medical Foundation, Victoriastiftelsen, the Orion Research Foundation, the Instrumentarium Science Foundation, the Paulo Foundation, the Päivikki and Sakari Sohlberg Foundation, the Juho Vainio Foundation, the Foundation of Finnish Pediatric Research in Finland, the Academy of Finland, the Sigrid Jusélius Foundation, the Swedish Research Council, the Novo Nordisk Foundation, Finska Läkaresällskapet, Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkléns minne and State funding for university-level health research in Finland. Funding for publication was received from the Helsinki University Library.