Genetic variants associated with circulating fibroblast growth factor 23

Cassianne Robinson-Cohen, Traci M. Bartz, Dongbing Lai, T. Alp Ikizler, Munro Peacock, Erik Imel, Erin D. Michos, Tatiana Foroud, Kristina Akesson, Kent D. Taylor, Linnea Malmgren, Kunihiro Matsushita, Maria Nethander, Joel Eriksson, Claes Ohlsson, Daniel Mellström, Myles Wolf, Osten Ljunggren, Fiona McGuigan, Jerome I. RotterMagnus Karlsson, Michael Econs, Joachim H. Ix, Pamela L. Lutsey, Bruce M. Psaty, Ian H. De Boer, Bryan R. Kestenbaum

Research output: Contribution to journalArticle

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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=3.0310224), 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.

Original languageEnglish (US)
Pages (from-to)2583-2592
Number of pages10
JournalJournal of the American Society of Nephrology
Volume29
Issue number10
DOIs
StatePublished - Oct 1 2018

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Single Nucleotide Polymorphism
Vitamin D
Phosphates
Genes
Kidney
fibroblast growth factor 23
Bone and Bones
Genome-Wide Association Study
Blood Group Antigens
Transferases
Phosphorus
Minerals
Meta-Analysis
Cohort Studies
Alleles
Genome
Hormones
Enzymes
Vitamin D3 24-Hydroxylase
1,25-dihydroxyvitamin D

ASJC Scopus subject areas

  • Nephrology

Cite this

Genetic variants associated with circulating fibroblast growth factor 23. / Robinson-Cohen, Cassianne; Bartz, Traci M.; Lai, Dongbing; Alp Ikizler, T.; Peacock, Munro; Imel, Erik; Michos, Erin D.; Foroud, Tatiana; Akesson, Kristina; Taylor, Kent D.; Malmgren, Linnea; Matsushita, Kunihiro; Nethander, Maria; Eriksson, Joel; Ohlsson, Claes; Mellström, Daniel; Wolf, Myles; Ljunggren, Osten; McGuigan, Fiona; Rotter, Jerome I.; Karlsson, Magnus; Econs, Michael; Ix, Joachim H.; Lutsey, Pamela L.; Psaty, Bruce M.; De Boer, Ian H.; Kestenbaum, Bryan R.

In: Journal of the American Society of Nephrology, Vol. 29, No. 10, 01.10.2018, p. 2583-2592.

Research output: Contribution to journalArticle

Robinson-Cohen, C, Bartz, TM, Lai, D, Alp Ikizler, T, Peacock, M, Imel, E, Michos, ED, Foroud, T, Akesson, K, Taylor, KD, Malmgren, L, Matsushita, K, Nethander, M, Eriksson, J, Ohlsson, C, Mellström, D, Wolf, M, Ljunggren, O, McGuigan, F, Rotter, JI, Karlsson, M, Econs, M, Ix, JH, Lutsey, PL, Psaty, BM, De Boer, IH & Kestenbaum, BR 2018, 'Genetic variants associated with circulating fibroblast growth factor 23', Journal of the American Society of Nephrology, vol. 29, no. 10, pp. 2583-2592. https://doi.org/10.1681/ASN.2018020192
Robinson-Cohen, Cassianne ; Bartz, Traci M. ; Lai, Dongbing ; Alp Ikizler, T. ; Peacock, Munro ; Imel, Erik ; Michos, Erin D. ; Foroud, Tatiana ; Akesson, Kristina ; Taylor, Kent D. ; Malmgren, Linnea ; Matsushita, Kunihiro ; Nethander, Maria ; Eriksson, Joel ; Ohlsson, Claes ; Mellström, Daniel ; Wolf, Myles ; Ljunggren, Osten ; McGuigan, Fiona ; Rotter, Jerome I. ; Karlsson, Magnus ; Econs, Michael ; Ix, Joachim H. ; Lutsey, Pamela L. ; Psaty, Bruce M. ; De Boer, Ian H. ; Kestenbaum, Bryan R. / Genetic variants associated with circulating fibroblast growth factor 23. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 10. pp. 2583-2592.
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title = "Genetic variants associated with circulating fibroblast growth factor 23",
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=3.0310224), 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.",
author = "Cassianne Robinson-Cohen and Bartz, {Traci M.} and Dongbing Lai and {Alp Ikizler}, T. and Munro Peacock and Erik Imel and Michos, {Erin D.} and Tatiana Foroud and Kristina Akesson and Taylor, {Kent D.} and Linnea Malmgren and Kunihiro Matsushita and Maria Nethander and Joel Eriksson and Claes Ohlsson and Daniel Mellstr{\"o}m and Myles Wolf and Osten Ljunggren and Fiona McGuigan and Rotter, {Jerome I.} and Magnus Karlsson and Michael Econs and Ix, {Joachim H.} and Lutsey, {Pamela L.} and Psaty, {Bruce M.} and {De Boer}, {Ian H.} and Kestenbaum, {Bryan R.}",
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T1 - Genetic variants associated with circulating fibroblast growth factor 23

AU - Robinson-Cohen, Cassianne

AU - Bartz, Traci M.

AU - Lai, Dongbing

AU - Alp Ikizler, T.

AU - Peacock, Munro

AU - Imel, Erik

AU - Michos, Erin D.

AU - Foroud, Tatiana

AU - Akesson, Kristina

AU - Taylor, Kent D.

AU - Malmgren, Linnea

AU - Matsushita, Kunihiro

AU - Nethander, Maria

AU - Eriksson, Joel

AU - Ohlsson, Claes

AU - Mellström, Daniel

AU - Wolf, Myles

AU - Ljunggren, Osten

AU - McGuigan, Fiona

AU - Rotter, Jerome I.

AU - Karlsson, Magnus

AU - Econs, Michael

AU - Ix, Joachim H.

AU - Lutsey, Pamela L.

AU - Psaty, Bruce M.

AU - De Boer, Ian H.

AU - Kestenbaum, Bryan R.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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=3.0310224), 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.

AB - 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=3.0310224), 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.

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