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Zheng, J.* ; Wheeler, E.* ; Pietzner, M.* ; Andlauer, T.F.M.* ; Yau, M.S.* ; Hartley, A.E.* ; Brumpton, B.M.* ; Rasheed, H.* ; Kemp, J.P.* ; Frysz, M.* ; Robinson, J.* ; Reppe, S.* ; Prijatelj, V.* ; Gautvik, K.M.* ; Falk, L.* ; Maerz, W.* ; Gergei, I.* ; Peyser, P.A.* ; Kavousi, M.* ; de Vries, P.S.* ; Miller, C.L.* ; Bos, M.* ; van der Laan, S.W.* ; Malhotra, R.* ; Herrmann, M.* ; Scharnagl, H.* ; Kleber, M.* ; Dedoussis, G.* ; Zeggini, E. ; Nethander, M.* ; Ohlsson, C.* ; Lorentzon, M.* ; Wareham, N.* ; Langenberg, C.* ; Holmes, M.V.* ; Davey Smith, G.* ; Tobias, J.H.*

Lowering of circulating sclerostin may increase risk of atherosclerosis and its risk factors: Evidence from a genome-wide association meta-analysis followed by Mendelian randomization.

Arthritis Rheum. 75, 1781-1792 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ld Score Regression; Susceptibility Loci; Romosozumab; Identification; Imputation; Frequency; Variants; Women
ISSN (print) / ISBN 0004-3591
e-ISSN 1529-0131
Journal Arthritis & Rheumatology
Quellenangaben Volume: 75, Issue: 10, Pages: 1781-1792 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
Grants European Research Area Network on Cardio-vascular Diseases (ERA-CVD) program" druggable-MI-targets"
Leducq Foundation"PlaqOmics"
National Heart, Lung, and Blood Institute(NHLBI), NIH
National Key Research and Development Program of China
Wellcome Trust
UK Medical Research Council
University of Bristol
NIH
Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation
Wild Family Foundation
American Heart Association
NHLBI, NIH
EU Horizon 2020 project TO_AI-TION
NHLBI
National Health and Medical Research Council (Australia) investigator grant
St. Olav's Hospital
Liaison Committee for Education, Research and Innovation in Central Norway
Research Council of Norway
University of Michigan
Faculty of Medicine and Health Sciences, NTNU