Genetic association between serum 25-hydroxyvitamin D levels and functional outcome after ischemic stroke

Previous observational studies suggest that serum 25-hydroxyvitamin D [25(OH)D] levels may associate with functional outcome after ischemic stroke. However, the causal relationship is not yet defined. Consequently, this study employed two-sample Mendelian Randomization (MR) to elucidate the causal association between serum 25(OH)D levels and functional outcome after ischemic stroke.

The genome-wide association study (GWAS) for serum 25(OH)D levels included 417,580 patients of European descent. The GWAS for functional outcome after ischemic stroke is from Genetics of Ischemic Stroke Functional Outcome meta-analysis. Post-stroke outcomes were evaluated using two sets of binary categorical variables (0-2 vs. 3-6 and 0-1 vs. 2-6), and also as ordered modified Rankin Scale (mRS) variables at 3 months. Two-sample MR was used to assess whether the exposure causally affects the outcome. Inverse Variance Weighted (IVW) was the primary method for our MR analysis, which was further supported by sensitivity analyses to ensure the robustness of the results.

The primary analysis using IVW method indicated no significant casual association between serum 25(OH)D levels and mRS (0-1) vs. mRS (2-6) at 3 months (OR = 0.914, 95% CI: 0.587-1.422, P = 0.69), mRS (0-2) vs. mRS (3-6) at 3 months (OR = 0.699, 95% CI: 0.477-1.025, P = 0.07), and mRS at 3 months (OR = 1.202, 95% CI: 0.875-1.650, P = 0.26). Additionally, after adjusting for stroke severity, the IVW analysis also showed no significant association between serum 25(OH)D levels and mRS (0-1) vs. mRS (2-6) at 3 months (OR = 0.93, 95% CI: 0.55-1.56, P = 0.78), mRS (0-2) vs. mRS (3-6) at 3 months (OR = 0.73, 95% CI: 0.47-1.13, P = 0.16), and mRS at 3 months (OR = 1.09, 95% CI: 0.77-1.54, P = 0.62). The results of the sensitivity analysis suggest that our findings are robust.

Our MR study offers no genetic evidence supporting the effects of serum 25(OH)D levels on functional outcomes after ischemic stroke. The associations observed in previous observational studies may be attributed to residual confounding factors and reverse causality.