Proxied therapeutic inhibition on sclerostin and atrial fibrillation risk

Figures

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  Fig. 1. The shared genetic architecture of circulating SOST with heel bone mineral density (eBMD) and atrial fibrillation (AF). The shared genetic architecture of circulating SOST with heel bone mineral density (eBMD) and atrial fibrillation (AF). A conditional quantile-quantile (QQ) plot for circulating SOST (N = 35,559) and eBMD (N = 377,585); B reverse conditional QQ plots for circulating SOST and eBMD; C conditional quantile-quantile (QQ) plot for circulating SOST and AF (N = 1,030,836); D reverse conditional quantile-quantile (QQ) plot for circulating SOST and AF.

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  Fig. 2. Association estimates for genetic variants around B4GALNT3 gene region. A Volcano plot of the Wald test results of each genetic variant for the association between circulating SOST pQTL and BMD. Regional association plots of flanking 5 kb region around the SOST and B4GALNT3 genes, based on multi-omics datasets: B SOST pQTL within B4GALNT3 gene region; C BMD QTL within B4GALNT3 gene region; D B4GALNT3 eQTL within B4GALNT3 gene region; E AF QTL within B4GALNT3 gene region. The x-axis denotes the physical position of each genetic variant on the chromosome specified, whereas the y-axis indicates the evidence of association, which was shown as -log10(Pvalue). AF atrial fibrillation, eBMD heel bone mineral density, eQTL expression quantitative trait locus, pQTL genotype–protein association.

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  Fig. 3. B4GALNT3 as a causal gene for regulation of SOST secretion. A The forest plot of the Summary-based Mendelian randomization result between elevated B4GALNT3 gene expression and circulating SOST level in three tissues. All analyses were conducted as two-sided statistical tests, and exact two-sided P values are reported. B Real-time quantitative PCR (qPCR) analysis after transfection of Saos-2 cells with three designed siRNAs targeting B4GALNT3. Representative blotting image (C) and statistical analyses (D) of western blot analysis of B4GALNT3 knockdown from three independent experiments. Representative blotting image (E) and statistical analyses (F) of western blot analysis of SOST protein secretion into the culture medium from three independent experiments. G, H Representative blotting image (E) and statistical analyses (F) of western blot analysis of SOST protein secretion into the culture medium after lenti-B4GALNT3 infection from three independent experiments. The statistical significance was assessed using one-way analysis of variance (ANOVA) with Dunnett’s post hoc test (B, D and F) or unpaired two-tailed Student’s t test (H), and results were shown as mean ± S.D. *p < 0.05,…

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  Fig. 4. Mendelian randomization estimates for the association between proxied SOST inhibition and BMD as well as AF. Mendelian randomization estimates for the association between proxied SOST inhibition and BMD as well as AF. A Forest plot of the association estimates of B4GALNT3 gene expression and SOST inhibition with bone mineral density using multi-omics datasets based on summary-based Mendelian randomization and Mendelian randomization analyses; B forest plot of the association estimates of B4GALNT3 gene expression and SOST inhibition with atrial fibrillation using multi-omics datasets based on summary-based Mendelian randomization, and Mendelian randomization analyses. 95% CI 95% confidence interval, MR Mendelian randomization, OR odds ratio, SE standard error.