Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

BackgroundFibroblast 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.MethodsWe 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.ResultsWe 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.ConclusionsCommon 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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Fibroblast Growth Factor 23 and Disordered Vitamin D Metabolism in Chronic Kidney Disease: Updating the “Trade-off” Hypothesis: Figure 1.

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.02640310 ◽

2010 ◽

Vol 5 (9) ◽

pp. 1710-1716 ◽

Cited By ~ 91

Author(s):

Orlando M. Gutiérrez

Keyword(s):

Chronic Kidney Disease ◽

Vitamin D ◽

Growth Factor ◽

Kidney Disease ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Trade Off

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The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune?Albright syndrome

Journal of Bone and Mineral Metabolism ◽

10.1007/s00774-004-0589-9 ◽

2005 ◽

Vol 23 (3) ◽

pp. 231-237 ◽

Cited By ~ 47

Author(s):

Takehisa Yamamoto ◽

Yasuo Imanishi ◽

Eiichi Kinoshita ◽

Yoshiko Nakagomi ◽

Nobuhiko Shimizu ◽

...

Keyword(s):

Vitamin D ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Mccune Albright Syndrome ◽

Albright Syndrome ◽

Mccune Albright

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Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

Endocrinology ◽

10.1210/en.2004-0233 ◽

2004 ◽

Vol 145 (11) ◽

pp. 5269-5279 ◽

Cited By ~ 241

Author(s):

Xiuying Bai ◽

Dengshun Miao ◽

Jiarong Li ◽

David Goltzman ◽

Andrew C. Karaplis

Keyword(s):

Vitamin D ◽

Growth Factor ◽

Transgenic Mice ◽

Fibroblast Growth Factor ◽

Calcium Homeostasis ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Dihydroxyvitamin D3 ◽

Circulating Levels

Abstract Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D3) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D3 production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.

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Regulation of serum 1,25(OH)2Vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4

AJP Renal Physiology ◽

10.1152/ajprenal.00740.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. F371-F377 ◽

Cited By ~ 62

Author(s):

Jyothsna Gattineni ◽

Katherine Twombley ◽

Regina Goetz ◽

Moosa Mohammadi ◽

Michel Baum

Keyword(s):

Vitamin D ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Serum Levels ◽

Phosphate Transport ◽

Fibroblast Growth ◽

Wild Type ◽

Baseline Serum ◽

Renal Phosphate Reabsorption

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)2Vitamin D3 levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)2Vitamin D3 levels remained elusive. To determine the FGFRs regulating 1,25(OH)2Vitamin D3 levels, we studied FGFR3−/−FGFR4−/− mice as these mice have shortened life span and are growth retarded similar to FGF23−/− and Klotho−/− mice. Baseline serum 1,25(OH)2Vitamin D3 levels were elevated in the FGFR3−/−FGFR4−/− mice compared with wild-type mice (102.2 ± 14.8 vs. 266.0 ± 34.0 pmol/l; P = 0.001) as were the serum levels of FGF23. Administration of recombinant FGF23 had no effect on serum 1,25(OH)2Vitamin D3 in the FGFR3−/−FGFR4−/− mice (173.4 ± 32.7 vs. 219.7 ± 56.5 pmol/l; vehicle vs. FGF23) while it reduced serum 1,25(OH)2Vitamin D3 levels in wild-type mice. Administration of FGF23 to FGFR3−/−FGFR4−/− mice resulted in a decrease in serum parathyroid hormone (PTH) levels and an increase in serum phosphorus levels mediated by increased renal phosphate reabsorption. These data indicate that FGFR3 and 4 are the receptors that regulate serum 1,25(OH)2Vitamin D3 levels in response to FGF23. In addition, when 1,25(OH)2Vitamin D3 levels are not affected by FGF23, as in FGFR3−/−FGFR4−/− mice, a reduction in PTH can override the effects of FGF23 on renal phosphate transport.

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