Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes

Marta Alcalde-Herraiz, JunQing Xie, Danielle Newby, Clara Prats, Dipender Gill, María Gordillo-Marañón, Daniel Prieto-Alhambra (), Martí Català and Albert Prats-Uribe
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Marta Alcalde-Herraiz: University of Oxford
JunQing Xie: University of Oxford
Danielle Newby: University of Oxford
Clara Prats: Universitat Politècnica de Catalunya
Dipender Gill: Imperial College London
María Gordillo-Marañón: University College London
Daniel Prieto-Alhambra: University of Oxford
Martí Català: University of Oxford
Albert Prats-Uribe: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Sclerostin inhibitors protect against osteoporotic fractures, but their cardiovascular safety remains unclear. We conducted a cis-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 25–85% 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.

Date: 2024
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DOI: 10.1038/s41467-024-53623-5

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