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.
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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, Davey Smith George, Tobias Jonathan H
Аннотация
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.