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

Jie Zheng*, Eleanor Wheeler, Maik Pietzner, Till F.M. Andlauer, Michelle S. Yau, April E. Hartley, Ben Michael Brumpton, Humaira Rasheed, John P. Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe, Vid Prijatelj, Kaare M. Gautvik, Louise Falk, Winfried Maerz, Ingrid Gergei, Patricia A. Peyser, Maryam Kavousi, Paul S. de VriesClint L. Miller, Maxime Bos, Sander W. van der Laan, Rajeev Malhotra, Markus Herrmann, Hubert Scharnagl, Marcus Kleber, George Dedoussis, Eleftheria Zeggini, Maria Nethander, Claes Ohlsson, Mattias Lorentzon, Nick Wareham, Claudia Langenberg, Michael V. Holmes, George Davey Smith*, Jonathan H. Tobias*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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. 


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. 


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. 


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. (Figure presented.).

Original languageEnglish
Pages (from-to)1781-1792
Number of pages12
JournalArthritis and Rheumatology
Issue number10
Early online date25 Apr 2023
Publication statusPublished - Oct 2023

Bibliographical note

Funding Information:
We are extremely grateful to all the families who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

Publisher Copyright:
© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.


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