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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

Journal article
Authors C. Robinson-Cohen
T. M. Bartz
D. B. Lai
T. A. Ikizler
M. Peacock
E. A. Imel
E. D. Michos
T. M. Foroud
K. Akesson
K. D. Taylor
L. Malmgren
K. Matsushita
Maria Nethander
Joel Eriksson
Claes Ohlsson
Dan Mellström
M. Wolf
O. Ljunggren
F. McGuigan
J. I. Rotter
M. Karlsson
M. J. Econs
J. H. Ix
P. L. Lutsey
B. M. Psaty
I. H. de Boer
B. R. Kestenbaum
Published in Journal of the American Society of Nephrology
Volume 29
Issue 10
Pages 2583-2592
ISSN 1046-6673
Publication year 2018
Published at Core Facilities, Bioinformatics
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 2583-2592
Language en
Links dx.doi.org/10.1681/asn.2018020192
Keywords human genetics, fibroblast growth factor 23, mineral metabolism, linked hypophosphatemic rickets, genome-wide association, bone-mineral, density, von-willebrand-factor, cardiovascular events, vitamin-d, phosphate homeostasis, parathyroid-hormone, kidney-function, elderly-men
Subject categories Urology and Nephrology, Medical Genetics

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 m(2) 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=3.0x10(-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.

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