Abstract
ABSTRACTIn 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 (β = 0.20, p = 4.6 × 10−49) and GALNT1 (β = 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 (β = –0.12, 95% confidence interval [CI] –0.20 to –0.05) and eBMD (β = –0.12, 95% CI –0.14 to –0.10), and a positive relationship with fracture risk (β = 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.
Highlights
Sclerostin is a glycoprotein produced by osteocytes, which is thought to play an important role in bone’s adaptive response to mechanical loading, acting within the local bone microenvironment to suppress bone formation.[1]
Serum sclerostin has been reported to increase in chronic kidney disease (CKD) and may contribute to the pathogenesis of chronic kidney disease–mineral and bone disorder (CKD‐MBD).(5) Serum sclerostin levels are higher in patients with cardiovascular disease and may predict cardiovascular mortality.[6]. A relationship with glucose metabolism has been suggested in light by reports of higher sclerostin levels in association with type 1 and type 2 diabetes mellitus in adolescents[7] and adults,(8) respectively
We looked up genomewide association study (GWAS) results in distinct cohorts to those used for the sclerostin GWAS, namely GEFOS in the case of femoral neck and lumbar spine bone mineral density (BMD; n = 32,961)(27) and UK Biobank in the case of estimated BMD[28] and fracture risk (n = 426,795).(29) In this initial analysis, sclerostin was treated as the exposure and bone traits as the outcomes, using sclerostin‐associated Single‐ nucleotide polymorphisms (SNPs) as the instrumental variables
Summary
Sclerostin is a glycoprotein produced by osteocytes, which is thought to play an important role in bone’s adaptive response to mechanical loading, acting within the local bone microenvironment to suppress bone formation.[1]. Serum sclerostin has been reported to increase in chronic kidney disease (CKD) and may contribute to the pathogenesis of chronic kidney disease–mineral and bone disorder (CKD‐MBD).(5) Serum sclerostin levels are higher in patients with cardiovascular disease and may predict cardiovascular mortality.[6] A relationship with glucose metabolism has been suggested in light by reports of higher sclerostin levels in association with type 1 and type 2 diabetes mellitus in adolescents[7] and adults,(8) respectively These changes may represent “off‐target” effects of sclerostin originating from bone, alternatively, sclerostin might act as an endocrine hormone, subject to regulation by as yet unidentified additional factors. Aside from extraskeletal target tissues, perturbations in serum sclerostin could conceivably affect the bone itself through consequent alterations of sclerostin levels within the local bone environment
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