(SLB-054) Genetically perturbed plasma sclerostin level and incident ischemic stroke

Background: There is a significant healthcare concern about lowering sclerostin levels due to the increased risk of an incident ischemic stroke. Currently, heterogeneity among ischemic stroke subtypes is not being taken into account, which makes it difficult to establish preventive strategies.

Objectives: To identify the causal effect of a change in plasma sclerostin levels on incident ischemic stroke and its subtypes.

Methods: We conducted a drug-target Mendelian randomization analysis to determine the impact of protein abundance on safety outcomes. First, we established a primary hypothesis that genetically perturbed plasma sclerostin level is causally associated with any ischemic stroke (AIS). We then established exploratory hypotheses that plasma sclerostin level could affect the risk of subtypes of AIS: cardiometabolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS). cis-protein quantitative trait loci (cis-pQTL) of sclerostin were acquired from summary statistics of the UK Biobank Pharma Proteomics Project (UKB-PPP). Linkage disequilibrium-based clumping procedure was conducted to select genetic instruments, followed by harmonization to the summary statistics from the GIGASTROKE consortium. We estimated the change in odds per stroke phenotypes per unit change in plasma sclerostin levels using the Wald ratio. For phenotypes that showed a statistically significant effect, we utilized the MEGASTROKE summary statistics to confirm replicability and robustness to sample overlap bias.

Results: We identified a single cis-acting genetic instrument perturbing the plasma sclerostin level. A significant effect of lowered sclerostin level on increased odds for AIS was observed (odds ratio [OR] per 1-unit decrease in sclerostin level: 1.32; 95% confidence interval [CI]: 1.03–1.68; P = 0.027). Additionally, among three subtypes of ischemic stroke, odds for LAS was significantly affected by sclerostin level under a Bonferroni-adjusted significance level (OR: 2.71; 95% CI: 1.31–5.61; P = 0.007). While no statistically significant effect on AIS was replicated, a trend-level association was replicated as the direction of effect was concordant with the result at the discovery phase (OR: 1.31; 95% CI: 0.94–1.83; P = 0.107). Meanwhile, both the direction and the statistical significance of the effect of lowered sclerostin level on LAS were replicated (OR: 2.38; 95% CI: 1.02–5.55; P = 0.045).

Conclusions: Lower plasma sclerostin levels may increase ischemic stroke risk, particularly LAS, suggesting the importance of monitoring atherosclerotic risk in patients receiving sclerostin-lowering therapies.