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Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures.

ABSTRACT: In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n?=?32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n?=?426,824) and fracture risk (n?=?426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (??=?0.20, p?=?4.6?×?10-49 ) and GALNT1 (? ?=?0.11 per G allele, p?=?4.4?×?10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (??=?-0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (??=?-0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (??=?0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

SUBMITTER: Zheng J

PROVIDER: S-EPMC6899787 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures.

Zheng Jie J Maerz Winfried W Gergei Ingrid I Kleber Marcus M Drechsler Christiane C Wanner Christoph C Brandenburg Vincent V Reppe Sjur S Gautvik Kaare M KM Medina-Gomez Carolina C Shevroja Enisa E Gilly Arthur A Park Young-Chan YC Dedoussis George G Zeggini Eleftheria E Lorentzon Mattias M Henning Petra P Lerner Ulf H UH Nilsson Karin H KH Movérare-Skrtic Sofia S Baird Denis D Elsworth Benjamin B Falk Louise L Groom Alix A Capellini Terence D TD Grundberg Elin E Nethander Maria M Ohlsson Claes C Davey Smith George G Tobias Jonathan H JH

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20190802 10

In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral ne ...[more]

PMID: 31170332

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Project description:BackgroundOsteoporosis, which is a bone disease, is characterized by low bone mineral density and an increased risk of fractures. The heel bone mineral density is often used as a representative measure of overall bone mineral density. Lipid metabolism, which includes processes such as fatty acid metabolism, glycerol metabolism, inositol metabolism, bile acid metabolism, carnitine metabolism, ketone body metabolism, sterol and steroid metabolism, etc., may have an impact on changes in bone mineral density. While some studies have reported correlations between lipid metabolism and heel bone mineral density, the overall causal relationship between metabolites and heel bone mineral density remains unclear.Objectiveto investigate the causal relationship between lipid metabolites and heel bone mineral density using two-sample Mendelian randomization analysis.MethodsSummary-level data from large-scale genome-wide association studies were extracted to identify genetic variants linked to lipid metabolite levels. These genetic variants were subsequently employed as instrumental variables in Mendelian randomization analysis to estimate the causal effects of each lipid metabolite on heel bone mineral density. Furthermore, metabolites that could potentially be influenced by causal relationships with bone mineral density were extracted from the KEGG and WikiPathways databases. The causal associations between these downstream metabolites and heel bone mineral density were then examined. Lastly, a sensitivity analysis was conducted to evaluate the robustness of the results and address potential sources of bias.ResultsA total of 130 lipid metabolites were analyzed, and it was found that acetylcarnitine, propionylcarnitine, hexadecanedioate, tetradecanedioate, myo-inositol, 1-arachidonoylglycerophosphorine, 1-linoleoylglycerophoethanolamine, and epiandrosterone sulfate had a causal relationship with heel bone mineral density (p < 0.05). Furthermore, our findings also indicate an absence of causal association between the downstream metabolites associated with the aforementioned metabolites identified in the KEGG and WikiPathways databases and heel bone mineral density.ConclusionThis work supports the hypothesis that lipid metabolites have an impact on bone health through demonstrating a causal relationship between specific lipid metabolites and heel bone mineral density. This study has significant implications for the development of new strategies to osteoporosis prevention and treatment.

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Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures.

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Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures.

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