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Higher Fibroblast Growth Factor 23 Levels Are Causally Associated With Lower Bone Mineral Density of Heel and Femoral Neck: Evidence From Two-Sample Mendelian Randomization Analysis.

ABSTRACT: Background: Previous observational studies have indicated that high levels of fibroblast growth factor 23 (FGF23), a phosphoric hormone that inhibits calcitriol synthesis, in the blood is associated with the reduced bone mineral density (BMD); however, whether this association is causal remains unclear. In this study, we conducted a Mendelian Random (MR) study to investigate whether the genetic predisposition of higher FGF23 levels was causally associated with lower BMD in adults. Methods: A two-sample MR was performed with five single nucleotide polymorphisms significantly associated with FGF23, selected as instrumental variables. Two-sample MR estimates were derived from summary-level data of large-sample genome-wide association studies for BMD and the levels of bone metabolism characteristics. Results: The two-sample MR analysis showed that for every 1-unit increase in the log-transformed blood FGF23 level (pg/mL), the decreased levels of adult heel BMD (? = -0.201, se = 0.084, P = 0.016) and femoral neck BMD (? = -0.286, se = 0.126, P = 0.022) were noted, indicative of a causal relationship based on the inverse variance weighting method. However, FGF23 levels were not correlated with adult lumbar spine BMD (? = -0.166, se = 0.193, P = 0.389), and forearm BMD (? = -0.186, se = 0.366, P = 0.610). Moreover, the two-sample MR analysis suggested that there was no evidence for associations between FGF23 and adult calcium, phosphorus, 25(OH)D, creatinine, and magnesium levels. Conclusions: This study suggests that there may be a causal relationship between blood FGF23 levels and BMD of the heel and femoral neck in adults; however, more investigations are necessary to determine whether FGF23 may be a potential biomarker and/or therapeutic target for diseases that affect bone mineralization.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7492544 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Higher Fibroblast Growth Factor 23 Levels Are Causally Associated With Lower Bone Mineral Density of Heel and Femoral Neck: Evidence From Two-Sample Mendelian Randomization Analysis.

Wang Yue Y Wang Hui H Chen Peizhan P

Frontiers in public health 20200902

<b>Background:</b> Previous observational studies have indicated that high levels of fibroblast growth factor 23 (FGF23), a phosphoric hormone that inhibits calcitriol synthesis, in the blood is associated with the reduced bone mineral density (BMD); however, whether this association is causal remains unclear. In this study, we conducted a Mendelian Random (MR) study to investigate whether the genetic predisposition of higher FGF23 levels was causally associated with lower BMD in adults. <b>Meth ...[more]

PMID: 32984251

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Project description:BackgroundAlterations in the brain cortical structures of patients with chronic kidney disease (CKD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of kidney damage on brain cortical structure.MethodsGenome-wide association studies summary data of estimated glomerular filtration rate (eGFR) in 480,698 participants from the CKDGen Consortium were used to identify genetically predicted eGFR. Data from 567,460 individuals from the CKDGen Consortium were used to assess genetically determined CKD; 302,687 participants from the UK Biobank were used to evaluate genetically predicted albuminuria. Further, data from 51,665 patients from the ENIGMA Consortium were used to assess the relationship between genetic predisposition and reduced eGFR, CKD, and progressive albuminuria with alterations in cortical thickness (TH) or surficial area (SA) of the brain. Magnetic resonance imaging was used to measure the SA and TH globally and in 34 functional regions. Inverse-variance weighted was used as the primary estimate whereas MR Pleiotropy RESidual Sum and Outlier, MR-Egger and weighted median were used to detect heterogeneity and pleiotropy.FindingsAt the global level, albuminuria decreased TH (β = -0.07 mm, 95% CI: -0.12 mm to -0.02 mm, P = 0.004); at the functional level, albuminuria reduced TH of pars opercularis gyrus without global weighted (β = -0.11 mm, 95% CI: -0.16 mm to -0.07 mm, P = 3.74×10-6). No pleiotropy was detected.InterpretationKidney damage causally influences the cortex structure which suggests the existence of a kidney-brain axis.FundingThis study was supported by the Science and Technology Planning Project of Guangdong Province (Grant No. 2020A1515111119 and 2017B020227007), the National Key Research and Development Program of China (Grant No. 2018YFA0902803), the National Natural Science Foundation of China (Grant No. 81825016, 81961128027, 81772719, 81772728), the Key Areas Research and Development Program of Guangdong (Grant No. 2018B010109006), Guangdong Special Support Program (2017TX04R246), Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, and Grants from the Guangdong Science and Technology Department (2020B1212060018).

Project description:BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Dataset Information

Higher Fibroblast Growth Factor 23 Levels Are Causally Associated With Lower Bone Mineral Density of Heel and Femoral Neck: Evidence From Two-Sample Mendelian Randomization Analysis.

Publications

Higher Fibroblast Growth Factor 23 Levels Are Causally Associated With Lower Bone Mineral Density of Heel and Femoral Neck: Evidence From Two-Sample Mendelian Randomization Analysis.

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