Proxied therapeutic inhibition on sclerostin and atrial fibrillation risk

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).

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.

We observed polygenic overlap between circulating SOST and eBMD as well as atrial fibrillation (AF). Trans-protein quantitative trait loci (pQTLs) around the B4GALNT3 gene, instead of the genetic variants across the genome, could be instrumental variables to proxy the therapeutic effect of SOST inhibition. Further, increasing level of B4GALNT3 gene expression in several tissues was associated with a decreased level of circulating SOST. Consistently, in vitro evidence validated that B4GALNT3 overexpression significantly decreased SOST protein secretion. Notably, increasing level of B4GALNT3 gene expression in the same tissues was also associated with increased eBMD and higher risk of AF. The proxied SOST inhibition (instrumented by B4GALNT3 genetic variants) had a significant causal effect on increased eBMD (β-coefficient=0.034, SE = 0.007, P = 2.81 × 10^-7) 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.

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.