Proxied therapeutic inhibition on sclerostin and atrial fibrillation risk

BACKGROUND: Pharmacological inhibition of sclerostin (SOST) is clinically applied to treat osteoporosis. However, large-scale randomized controlled trials have reported conflicting findings regarding the cardiovascular effects of SOST inhibition. This study aimed to evaluate whether sustained SOST inhibition, mimicked by instrumental genetic variants, is associated with the altered risk of cardiovascular diseases (CVDs). METHODS: The individual-level genomic data were obtained from the UK Biobank, including 377,585 participants in the genome wide association study (GWAS) for estimated heel bone mineral density (eBMD). Summary-level genetic data for CVDs were retrieved from publicly available GWASs, with sample sizes ranging from 332,477 to 1,030,836 participants. The conditional quantile-quantile (QQ) plot was used to visualize the genetic pleiotropy between circulating SOST, eBMD and CVDs. By integrating genetic, transcriptomic, and proteomic data, Mendelian randomization was performed to assess the relationship between exposures and CVDs. RESULTS: ) and increased risk of AF (OR = 1.353, 95%CI = 1.077-1.701, P = 0.009). The results were replicated in the MR analyses with different instrumental variables based on different linkage disequilibrium (LD) thresholds. CONCLUSIONS: This multi-omics study suggested that reduced circulating SOST was associated with an increased risk of AF, which warrants attention in patients undergoing SOST inhibition treatment.