Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zheng, J; Wheeler, E; Pietzner, M; Andlauer, TFM; Yau, MS; Hartley, AE; Brumpton, BM; Rasheed, H; Kemp, JP; Frysz, M; Robinson, J; Reppe, S; Prijatelj, V; Gautvik, KM; Falk, L; Maerz, W; Gergei, I; Peyser, PA; Kavousi, M; de, Vries, PS; Miller, CL; Bos, M; van, der, Laan, SW; Malhotra, R; Herrmann, M; Scharnagl, H; Kleber, M; Dedoussis, G; Zeggini, E; Nethander, M; Ohlsson, C; Lorentzon, M; Wareham, N; Langenberg, C; Holmes, MV; Davey, Smith, G; Tobias, JH.
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.
ARTHRITIS RHEUMATOL. 2023; 75(10): 1781-1792.
Doi: 10.1002/art.42538
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- Co-Autor*innen der Med Uni Graz
- Herrmann Markus
- März Winfried
- Scharnagl Hubert
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Genome-Wide Association Study - administration & dosage
- Diabetes Mellitus, Type 2 - genetics
- Mendelian Randomization Analysis - administration & dosage
- Atherosclerosis - genetics, complications
- Myocardial Infarction - etiology
- Risk Factors - administration & dosage
- Hypertension - administration & dosage
- Polymorphism, Single Nucleotide - administration & dosage