Effect of genetically proxied plasma sclerostin levels on the risk of ischemic stroke: A drug-target Mendelian randomization study.

A single cis-acting genetic instrument perturbing plasma sclerostin levels was identified for use as the Mendelian randomization instrument.

• The study used a drug-target Mendelian randomization design focusing on cis-acting variants near the SOST gene.
• Only a single cis-acting genetic instrument was identified for perturbing plasma sclerostin levels.
• This instrument was used to proxy the effect of sclerostin-lowering interventions such as romosozumab.

Reduced plasma sclerostin levels were significantly associated with increased odds of any ischemic stroke (AIS).

• Odds ratio per 1-unit decrease in sclerostin levels: 1.32.
• 95% confidence interval: 1.03–1.68.
• P = .027.
• This finding supported the primary hypothesis that genetically perturbed plasma sclerostin levels are causally associated with any ischemic stroke.

Reduced plasma sclerostin levels were significantly associated with increased odds of large artery stroke (LAS) under Bonferroni-adjusted significance.

• Odds ratio per 1-unit decrease in sclerostin levels: 2.71.
• 95% confidence interval: 1.31–5.61.
• P = .007, which met the Bonferroni-adjusted significance threshold.
• LAS showed the strongest effect among the three ischemic stroke subtypes examined (cardiometabolic stroke, large artery stroke, and small vessel stroke).

No statistical evidence of confounding by linkage disequilibrium was observed for either AIS or LAS in Bayesian colocalization analyses.

• For AIS, the posterior probability of hypothesis H3 (two distinct causal variants) was PP.H3 = 4.13 × 10⁻³.
• For LAS, PP.H3 = .0104.
• Low PP.H3 values indicate that confounding by linkage disequilibrium was unlikely for both phenotypes.
• Bayesian colocalization analyses were conducted only for phenotypes showing statistically significant effects.

Sclerostin levels did not show statistically significant effects on cardiometabolic stroke or small vessel stroke.

• Three ischemic stroke subtypes were examined as exploratory hypotheses: cardiometabolic stroke, large artery stroke, and small vessel stroke.
• Only large artery stroke reached statistical significance under Bonferroni correction.
• Cardiometabolic stroke and small vessel stroke did not show statistically significant associations with sclerostin levels.

Previous observational studies and post hoc analyses of randomized trials had left the causal link between sclerostin-lowering interventions and ischemic stroke uncertain.

• The study motivation was the limitations of prior observational evidence and post hoc randomized trial analyses.
• The drug-target Mendelian randomization approach was used to overcome these limitations and better approximate causal inference.
• Sclerostin-reducing therapies such as romosozumab are used clinically, making cerebrovascular risk an important safety consideration.