Abstract
Background
We aimed to establish the causal effects of lowering sclerostin, target of the anti-osteoporosis 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 examine causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.
Results
18 conditionally independent variants were associated with circulating sclerostin. Of these, one cis signal in SOST and three trans signals in B4GALNT3, RIN3 and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. These four variants were selected as genetic instruments. MR using the cis-SNPs suggested lower sclerostin increased risk of hypertension, type 2 diabetes (T2DM) (OR=1.26; 95%CI=1.08 to 1.48) and myocardial infarction (MI) (OR=1.31, 95% CI=1.183 to 1.45); sclerostin lowering was also suggested to increase extent of coronary artery calcification (CAC) (β=0.74, 95%CI=0.33 to 1.15), levels of apoB (β=0.07; 95%CI=0.04 to 0.10) and triglycerides (β=0.18; 95%CI=0.13 to 0.24), and to reduce HDL-C levels (β=-0.14; 95%CI=-0.17 to -0.10). MR using both cis and trans instruments also suggested that lower sclerostin increased hypertension risk (odds ratio [OR]=1.09, 95%CI=1.04 to 1.15), but otherwise had attenuated effects.
Conclusions
This study provides genetic evidence to suggest that lower levels of sclerostin may increase risk of hypertension, T2DM, MI, and extent of CAC, and lead to an atherogenic lipid profile. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.
