Genetic Variants Associated with Circulating Fibroblast Growth Factor 23
Year: 2018
Type: review
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 =3.0×10 −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.
Authors: Cassianne Robinson-Cohen, Traci M. Bartz, Dongbing Lai, T. Alp Ikizler, Munro Peacock, Erik A. Imel, Erin D. Michos, Tatiana M. 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. Rotter, Magnus Karlsson, Michael J. Econs, Joachim H. Ix, Pamela L. Lutsey, Bruce M. Psaty, Ian H. de Boer, Bryan R. Kestenbaum
Institutions: Vanderbilt University Medical Center, Indiana University Indianapolis, Johns Hopkins University, Johns Hopkins Medicine, Lund University, Skåne University Hospital, University of California, Los Angeles, The Lundquist Institute, Los Angeles Medical Center, Harbor–UCLA Medical Center, University of Gothenburg, Duke University, Duke Medical Center, Duke Clinical Research Institute, Uppsala University, University of California San Diego, VA San Diego Healthcare System, University of Minnesota, Kaiser Permanente Washington Health Research Institute, University of Washington
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Novo Nordisk Fonden, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1052397333, G1135917780, Multi-Ethnic Study of Atherosclerosis (MESA) Study, G1220223050, G1243299691, MESA, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, Individual response to vitamin D treatment, G1409423729, Osteoporotic Fractures in Men (MrOS) - Minneapolis, G1493513681, G1527150935, CORONARY HEART DISEASE AND STROKE, G1686417863, G1691174148, UCLA Clinical and Translational Science Institute, G173303992, Wake Forest Clinical and Translational Science Award, G1941623656, Oregon Clinical and Translational Research Institute, Genome-wide case-only study of antihypertensive drug-gene interactions, Parathyroid Hormone: Genetic Architecture and Clinical Consequences, Osteoporatic Fractures in Men (MrOS), Rare variants and NHLBI traits in deeply phenotyped cohorts, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G2262782284, G232264632, G2391884931, MESA, Institute for Clinical and Translational Research (UL1), MESA Family Study, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G2663518188, General Clinical Research Center, G2818629771, MESA, FGF23 in Pediatric Phosphate Physiology and X-linked Hypophosphatemic Rickets., SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, G3045517347, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, G3114902838, Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium, G3220743633, G3256118428, MESA Family Study, G3342643523, G3410686264, G3462919067, CHS research resources for the cardiovascular health of older adults, Osteoporotic Fractures in Men (Mr. Os) Palo Alto, G3647016462, G3682927731, G3687594596, GWA for Gene-Environment Interaction Effects Influencing CHD, MESA, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, G399481048, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), G4512137732, Osteoporotic Fractures in Men (MrOS) - Administrative Center, G457330776, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA Family Study, MESA, Indiana Clinical and Translational Science Institute (UL1), MESA Family Study, G5088122703, G5108002584, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G5479317095, Epidemiology of Venous Thrombosis and Pulmonary Embolism, G567847597, G5787256936, G581887176, CHARGE consortium: omics discovery for CVD and aging phenotypes, The Effects of Iron Status on FGF23 Metabolism and Bone Health., CHS Events Follow-up Study, G6095866717, G6226795708, G6359107525, Institute for Clinical and Translational Research, MESA, G6514094751, G6548750934, Osteoporotic Fractures in Men (Mr.OS), CHS-Transition Phase, SNP HEALTH ASSOCIATION RESOURCE (SHARE), Osteoporotic Fractures in Men (MrOS) - San Francisco Coordinating Center, Osteoporotic Fractures in Men (MrOS) - Portland, G7176672723, MESA Family Study, MESA, Osteoporotic Fractures in Men_MrOS Renewal_Birmingham, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), Clinical and Translational Science Award, Serum Vitamin D and Cardiovascular Disease Risk in the Biethnic ARIC Cohort, G8267674335, Identification of genes that affect peak BMD in men and women, Genetic Determinants of Bone Fragility, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, UCLA Clinical and Translational Science Institute, Indiana Core Center for Clinical Research in Musculoskeletal Health
OpenAlex ID: W2891109199