Causal Association of Iron Status With Functional Outcome After Ischemic Stroke

Abstract

BACKGROUND: Iron status has been associated with functional outcomes after ischemic stroke (IS). Nonetheless, this association may be affected by confounders. We perform Mendelian randomization to clarify the causal association between iron status and functional outcome after IS. METHODS: We obtained summary-level statistics related to iron status biomarkers from a meta-analysis of a gene-wide association study conducted by the Genetics of Iron Status Consortium, which included 11 discovery cohorts and 8 replication cohorts. We also took genetic variants related to 4 biomarkers of iron status from combining gene-wide association study results of Iceland, the United Kingdom, and Denmark to perform a replicate Mendelian randomization analysis. This data set included 4 iron status biomarkers, namely, ferritin, total iron binding capacity, iron, and transferrin saturation (TSAT). The confounders in these data sets have been adjusted to mitigate the collider bias. We acquired summary statistics data sets for functional outcomes following IS from the gene-wide association study meta-analysis conducted by the Genetics of Ischemic Stroke Functional Outcome Consortium. The genetic estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Scale score, including 3741 cases with good functional outcomes (modified Rankin Scale score, 0–2) and 2280 subjects with poor functional outcomes poststroke (modified Rankin Scale score, 3–6). Inverse variance weighting was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: Reported with odds ratios (ORs) of stroke outcome with per SD unit increase in genetically determined iron status biomarker, TSAT and iron were associated with poor functional outcome after IS (TSAT: OR, 1.36 [95% CI, 1.23–1.50]; P =2.27×10 − 9 ; iron: OR, 1.44 [95% CI, 1.13–1.85]; P =0.0033). In replicate Mendelian randomization analysis, the detrimental effects of iron on poor functional outcome after IS remained stable (OR, 1.60 [95% CI, 1.24–2.08]; P =0.0003). In the meta-analysis, iron and TSAT were associated with poor functional outcomes after IS (TSAT: OR meta , 1.35 [95% CI, 1.23–1.48]; iron: OR meta , 1.51 [95% CI, 1.27–1.81]). Through sensitivity analyses and reverse Mendelian randomization analyses, we confirmed the robustness of the results. CONCLUSIONS: Our study provides evidence suggesting a potential causal relationship between iron status and poor functional outcomes after IS. Future studies are required to illuminate the underlying mechanism.