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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.

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 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=3.0×10-24), 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.

SUBMITTER: Robinson-Cohen C

PROVIDER: S-EPMC6171267 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.

Robinson-Cohen Cassianne C Bartz Traci M TM Lai Dongbing D Ikizler T Alp TA Peacock Munro M Imel Erik A EA Michos Erin D ED Foroud Tatiana M TM Akesson Kristina K Taylor Kent D KD Malmgren Linnea L Matsushita Kunihiro K Nethander Maria M Eriksson Joel J Ohlsson Claes C Mellström Daniel D Wolf Myles M Ljunggren Osten O McGuigan Fiona F Rotter Jerome I JI Karlsson Magnus M Econs Michael J MJ Ix Joachim H JH Lutsey Pamela L PL Psaty Bruce M BM de Boer Ian H IH Kestenbaum Bryan R BR

Journal of the American Society of Nephrology : JASN 20180914 10

<h4>Background</h4>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.<h4>Methods</h4>We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among ...[more]

PMID: 30217807

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Project description:ObjectiveFibroblast growth factor 23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and is associated with coronary artery calcification, and has been implicated in the pathogenesis of cardiovascular disease. The aim of this study was to determine whether circulating FGF23 concentration is independently associated with the severity and extent of coronary artery disease in patients undergoing coronary angiography.MethodA cross-sectional design was used to examine the relationship between serum FGF23 and the severity and extent of coronary artery stenosis in 2076 patients undergoing coronary angiography (1263 male and 813 female, mean aged 62.5 years). Subgroup analyses were performed to assess the associations between FGF23 and coronary arterial plaque characteristics evaluated by intravascular ultrasound and 12-month incidence of target vessel revascularization (TVR) and target lesion revascularization (TLR).FindingsWe found a stepwise increase of serum FGF23 concentrations in patients with mild, moderate, severe stenosis or with increased number of stenotic vessels compared with those without stenosis (P<0.001). Serum FGF23 concentration was positively correlated with stenosis scores as the global index of the severity and extent of coronary artery stenosis in both male and female (r = 0.315 and r = 0.291, P<0.001). In multiple regression analyses, serum FGF23 concentration was a significant determinant of the stenosis scores independent of other traditional risk factors (standardized β = 0.326, P<0.001). Furthermore, subgroup analyses found FGF23 was significantly associated with plaque and dense calcium volumes. Multiple logistic regression analyses showed that serum FGF23 levels were significantly independent predictors of TVR and TLR.ConclusionsWe report an independent association between circulating FGF23 concentration and the severity and extent of coronary artery stenosis in the coronary angiographic patients. Future studies are needed to elucidate the potential biological mechanisms and whether FGF23 is a modifiable cardiovascular risk factor.

Dataset Information

Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.

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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.

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