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We conducted a\n                    <jats:italic>cis<\/jats:italic>\n                    -Mendelian randomisation analysis to estimate the causal effect of sclerostin levels on cardiovascular risk factors. We meta-analysed three GWAS of sclerostin levels including 49,568 Europeans and selected 2 SNPs to be used as instruments. We included heel bone mineral density and hip fracture risk as positive control outcomes. Public GWAS and UK Biobank patient-level data were used for the study outcomes, which include cardiovascular events, risk factors, and biomarkers. Lower sclerostin levels were associated with higher bone mineral density and 85% reduction in hip fracture risk. However, genetically predicted lower sclerostin levels led to 25\u201385% excess coronary artery disease risk, 40% to 60% increased risk of type 2 diabetes, and worse cardiovascular biomarkers values, including higher triglycerides, and decreased HDL cholesterol levels. Results also suggest a potential (but borderline) association with increased risk of myocardial infarction. Our study provides genetic evidence of a causal relationship between reduced levels of sclerostin and improved bone health and fracture protection, but increased risk of cardiovascular events and risk factors.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-53623-5","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T18:21:14Z","timestamp":1731522074000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes"],"prefix":"10.1038","volume":"15","author":[{"given":"Marta","family":"Alcalde-Herraiz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0040-0042","authenticated-orcid":false,"given":"JunQing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Newby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1398-7559","authenticated-orcid":false,"given":"Clara","family":"Prats","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-7078","authenticated-orcid":false,"given":"Dipender","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2993-6577","authenticated-orcid":false,"given":"Mar\u00eda","family":"Gordillo-Mara\u00f1\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3950-6346","authenticated-orcid":false,"given":"Daniel","family":"Prieto-Alhambra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart\u00ed","family":"Catal\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1202-9153","authenticated-orcid":false,"given":"Albert","family":"Prats-Uribe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,13]]},"reference":[{"key":"53623_CR1","doi-asserted-by":"publisher","unstructured":"Salari N., et al. Global prevalence of osteoporosis among the world older adults: a comprehensive systematic review and meta-analysis. J. Orthop. Surg. Res. 16, https:\/\/doi.org\/10.1186\/s13018-021-02821-8 (2021).","DOI":"10.1186\/s13018-021-02821-8"},{"key":"53623_CR2","doi-asserted-by":"publisher","first-page":"882241","DOI":"10.3389\/fendo.2022.882241","volume":"13","author":"Y Shen","year":"2022","unstructured":"Shen, Y. et al. The Global Burden of Osteoporosis, Low Bone Mass, and Its Related Fracture in 204 Countries and Territories, 1990-2019. Front. Endocrinol. (Lausanne) 13, 882241 (2022).","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"53623_CR3","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1007\/s00198-022-06454-3","volume":"33","author":"PL Xiao","year":"2022","unstructured":"Xiao, P. L. et al. Global, regional prevalence, and risk factors of osteoporosis according to the World Health Organization diagnostic criteria: a systematic review and meta-analysis. 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His research group has received consultancy fees from Astra Zeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners and UCB Biopharma have funded or supported training programmes organised by DPA\u2019s department. The views expressed in this study are the personal views of MGM and do not represent the views of her current employer, the European Medicines Agency. All other authors declare no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All participants provided informed consent to participate in each one of the GWAS we have used. UK Biobank received ethical approval from the North West Multi-centre Research Ethics Committee (REC reference: 16\/NW\/0274). All participants provided informed consent to participate.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"<!--Emphasis Type='Bold' removed-->Ethics approval & consent to participate"}}],"article-number":"9832"}}