Abstract 133: Associations of Genetically Predicted Iron Status and Ischemic Stroke Subtypes: A Mendelian Randomization Study

Abstract

Mendelian randomization (MR) studies suggest a causal effect of Fe status on ischemic stroke (IS). It is currently unknown if these associations are confounded by pleiotropic effects of the instrumental variables (IV) on cardiovascular disease (CVD) risk factors, such as low-density lipoprotein cholesterol (LDL), diastolic blood pressure (DBP), and body mass index (BMI). We aimed to investigate the effect of iron (Fe) status on risk of IS subtypes (cardioembolic (CES), small vessel (SVS), and large artery atherosclerotic (LAS)) controlling for CVD risk factors. Fe biomarker IVs (total Fe binding capacity (TIBC), transferrin saturation (TSAT), serum Fe (SI), serum ferritin (SF)) were selected from a European GWAS (n=198K-258K) and filtered based on genome-wide significance ( P <5e -8 ), F-statistic>10, R 2 <0.001, minor allele frequency >1%, and consistent effect direction for all Fe traits. We performed univariate two-sample MR of each Fe trait on IS subtypes from MEGASTROKE (n cases: CES=7,193; SVS =5,386; LAS= 4,373) and implemented multivariate MR conditioning on LDL, DBP, and BMI from the UK Biobank. Estimates are expressed as odds ratio [95%CI] per SD unit increase in Fe. Univariate MR showed a detrimental effect of higher Fe status on CES, no effect on SVS, and a protective effect on LAS across all Fe markers ( Figure 1 ). The negative effect of Fe status on CES persisted when conditioning on LDL (TSAT: 1.17 [1.03-1.34]; TIBC: 0.84 [0.71-0.98]), DBP (TSAT: 1.15 [1.01-1.31]; TIBC: 0.82 [0.70-0.96]), or BMI (TSAT: 1.18 [1.04-1.34]; TIBC: 0.82 [0.70-0.95]) (all P <0.05). However, the apparent positive effect of Fe status on LAS disappeared when conditioning on CVD risk factors ( Figure 1 ), particularly LDL (all P <0.05). Higher Fe status is associated with a greater risk of CES independent of CVD risk factors. These findings support the role of Fe status as a modifiable risk factor for CES. Future studies are needed to assess the mechanisms mediating this effect.