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

Authors

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 Vries
Clint 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

Publication Date

10-1-2023

Journal

Arthritis & Rheumatology

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

Humans, Genome-Wide Association Study, Diabetes Mellitus, Type 2, Mendelian Randomization Analysis, Atherosclerosis, Myocardial Infarction, Risk Factors, Hypertension, Polymorphism, Single Nucleotide