Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

J Am Soc Nephrol. 2018 Oct;29(10):2583-2592. doi: 10.1681/ASN.2018020192. Epub 2018 Sep 14.

Abstract

Background: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.

Methods: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.

Results: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10-24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.

Conclusions: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

Keywords: fibroblast growth factor 23; human genetics; mineral metabolism.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Black People / genetics
  • Cohort Studies
  • Female
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / blood*
  • Genome-Wide Association Study
  • Humans
  • Kidney / metabolism
  • Male
  • Phosphates / metabolism
  • Polymorphism, Single Nucleotide*
  • RGS Proteins / genetics*
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / genetics
  • Vitamin D / metabolism
  • Vitamin D3 24-Hydroxylase / genetics*
  • White People / genetics

Substances

  • FGF23 protein, human
  • Phosphates
  • RGS Proteins
  • RGS14 protein, human
  • SLC34A1 protein, human
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Vitamin D
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase

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