Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

Research output: Contribution to journalArticle

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.

Details

Authors
  • Cassianne Robinson-Cohen
  • Traci M Bartz
  • Dongbing Lai
  • T Alp Ikizler
  • Munro Peacock
  • Erik A Imel
  • Erin D Michos
  • Tatiana M Foroud
  • Kent D Taylor
  • Kunihiro Matsushita
  • Maria Nethander
  • Joel Eriksson
  • Claes Ohlsson
  • Daniel Mellström
  • Myles Wolf
  • Osten Ljunggren
  • Jerome I Rotter
  • Michael J Econs
  • Joachim H Ix
  • Pamela L Lutsey
  • Bruce M Psaty
  • Ian H de Boer
  • Bryan R Kestenbaum
Organisations
External organisations
  • Skåne University Hospital
  • University of Minnesota system
  • University of Washington, Seattle
  • Indiana University
  • Vanderbilt University Medical Center
  • Johns Hopkins University School of Medicine
  • University of California, Los Angeles
  • Johns Hopkins University
  • University of Gothenburg
  • Duke University
  • Uppsala University
  • University of California System
  • University of California, San Diego
  • Kaiser Permanente Research Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)2583-2592
Number of pages10
JournalJournal of the American Society of Nephrology : JASN
Volume29
Issue number10
Publication statusPublished - 2018 Oct
Publication categoryResearch
Peer-reviewedYes