Associations between genetically predicted iron status and cardiovascular disease risk: A Mendelian randomization study

Alexa Barad; Andrew G Clark; Kimberly O O'Brien; Eva K Pressman

doi:10.1101/2024.02.05.24302373

Associations between genetically predicted iron status and cardiovascular disease risk: A Mendelian randomization study

medRxiv [Preprint]. 2024 Feb 6:2024.02.05.24302373. doi: 10.1101/2024.02.05.24302373.

Authors

Alexa Barad¹, Andrew G Clark^{2

3}, Kimberly O O'Brien¹, Eva K Pressman⁴

Affiliations

¹ Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA.
² Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA.
³ Department of Computational Biology, Cornell University, Ithaca, New York, USA.
⁴ Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, New York, USA.

Abstract

Background: Mendelian randomization (MR) studies suggest a causal effect of iron (Fe) status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables (IV) on CVD risk factors. We aimed to investigate the effect of Fe status on CVD risk controlling for CVD risk factors.

Methods: Fe biomarker IVs (total Fe binding capacity (TIBC, n=208,422), transferrin saturation (TSAT, n=198,516), serum Fe (SI, n=236,612), ferritin (n=257,953)) were selected from a European GWAS meta-analysis. We performed two-sample univariate (UV) MR of each Fe trait on CVD outcomes (all-cause ischemic stroke (IS), cardioembolic IS (CES), large artery IS (LAS), small vessel IS (SVS), and coronary heart disease (CHD)) from MEGASTROKE (n=440,328) and CARDIoGRAMplusC4D (n=183,305). We then implemented multivariate (MV) MR conditioning on six CVD risk factors from independent European samples to evaluate their potential confounding and/or mediating effects on the observed Fe-CVD associations.

Results: With UVMR analyses, we found higher genetically predicted Fe status to be associated with a greater risk of CES (TSAT: OR 1.17 [95%CI 1.03, 1.33], SI: OR 1.21 [ 95%CI 1.02, 1.44]; TIBC: OR 0.81 [95%CI 0.69, 0.94]). The detrimental effects of Fe status on CES risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure (DBP) to mediate between 7.1-8.8% of the total effect of Fe status on CES incidence. While UVMR initially suggested a protective effect of Fe status on LAS and CHD, MVMR analyses factoring CVD risk factors revealed a complete annulment of this perceived protective effect (all P>0.05).

Discussion: Higher Fe status was associated with a greater risk of CES independent of CVD risk factors, and this effect was partly mediated by DBP. These findings support a role of Fe status as a modifiable risk factor for CES.

Keywords: Mendelian randomization; cardioembolic stroke risk; iron status; ischemic stroke.

Publication types

Preprint

Grants and funding

R01 DK122216/DK/NIDDK NIH HHS/United States