Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.

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

Journal: Journal of the American Society of Nephrology : JASN 2019;29(10):2583-2592

PMID: 30217807

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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 m 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 (=3.0×10), lies upstream of , 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 and upstream of (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 , 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.

Address: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; [email protected].; Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine.; Departments of Medical and Molecular Genetics and.; Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.; Medicine, Indiana University, Indianapolis, Indiana.; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland.; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Science Malmö, Lund University, Malmö, Sweden.; Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden.; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, California.; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and.; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland.; Department of Medicine, Bioinformatics Core Facility and.; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.; Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, Uppsala, Sweden.; Departments of Medical and Molecular Genetics and.; Medicine, Indiana University, Indianapolis, Indiana.; Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, California.; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, California.; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.; Cardiovascular Health Research Unit, Departments of Epidemiology, Health Services and Medicine, and.; Kaiser Permanente Washington Health Research Institute, Seattle, Washington.; Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.

DOI: 10.1681/ASN.2018020192