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.
Bibliographical noteFunding Information:
C.R.-C.’s work is supported by K01DK09019 from the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, R01HL086694, National Human Genome Research Institute grant U01HG004402, and National Institutes of Health (NIH) contract HHSN268200625226C. FGF23 measurements were supported by R01HL103706. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. The work within the Indiana Sisters cohort was supported by NIH grants R01AG041517, P30AR072581, P01AG018397, R21AR061078, K23AR057096, UL1RR025761, and M01RR00750 and by a donation from the Scottish Rite of Indianapolis Foundation. Gen-otyping services were provided by the Center for Inherited Disease Research, which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract HHSN268200782096C). This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. The Osteoporotic Fractures in Men (MrOS) Study is supported by the following NIH institutes: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and the NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. MrOS Sweden is supported by the Swedish Research Council, Läkarutbildningsavtalet/Avtal om läkarutbildning och forskning research grants in Gothenburg, and the King Gustav V and Queen Victoria Frimurarestiftelse Research Foundation. The work was also supported by the UK Medical Research Council Lifecourse Epidemiology Unit (4050502589). The Osteoporosis Prospective Risk Assessment study was supported by Swedish Research Council grants (K2009-53X-14691-07-3 through K2015-52X-14691-13-4). This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL085251, R01HL105756, R01HL103612, R01HL120393, and U01HL130114, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR001881, and the NIDDK Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Support for FGF23 measurements was provided by American Heart Association grant 0575021N to J.H.I. Infrastructure for the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium is supported in part by the NHLBI grant R01HL105756. The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA Single Nucleotide Polymorphism Health Association Resource (SHARe) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Funding for FGF23 measurements was provided by R01HL096875. Support is also provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, and R01HL071259; by the National Center for Research Resources, grant UL1RR033176; the National Center for Advancing Translational Sciences, grant UL1TR001881; and the NIDDK Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0.