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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

Zheng, Jie
; 
Wheeler, Eleanor
; 
Pietzner, Maik
; 
Andlauer, Till F. M.
; 
Yau, Michelle S.
; 
Hartley, April E.
; 
Brumpton, Ben Michael
; 
Rasheed, Humaira
; 
Kemp, John P.
; 
Frysz, Monika
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Author
Zheng, Jie
Wheeler, Eleanor
Pietzner, Maik
Andlauer, Till F. M.
Yau, Michelle S.
Hartley, April E.
Brumpton, Ben Michael
Rasheed, Humaira
Kemp, John P.
Frysz, Monika
Robinson, Jamie
Reppe, Sjur
Prijatelj, Vid
Gautvik, Kaare M.
Falk, Louise
Maerz, Winfried
Gergei, Ingrid
Peyser, Patricia A.
Kavousi, Maryam
de Vries, Paul S.
Miller, Clint L.
Bos, Maxime
van der Laan, Sander W.
Malhotra, Rajeev
Herrmann, Markus
Scharnagl, Hubert
Kleber, Marcus
Dedoussis, George
Zeggini, Eleftheria
Nethander, Maria
Ohlsson, Claes
Lorentzon, Mattias
Wareham, Nick
Langenberg, Claudia
Holmes, Michael V.
Smith, George Davey
Tobias, Jonathan H.
Abstract
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.
Keywords
Date
2023
Type
Journal article
Journal
Arthritis and Rheumatology
Book
Volume
75
Issue
10
Page Range
1781-1792
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Collections
Mary MacKillop Institute for Health Research
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URI
https://hdl.handle.net/20.500.14802/25409
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DOI
10.1002/art.42538
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Open Access Status
Published as ‘gold’ (paid) open access
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Open
Open
Notes
© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.