The effect of genetically determined iron status on risk of venous thromboembolism and carotid atherosclerotic disease: A Mendelian randomization study

Background: Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this work was to investigate the effect of genetically determined iron status on carotid intima-media thickness (cIMT), carotid plaque and venous thromboembolism (VTE) using Mendelian randomization (MR). Methods and Results: Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48,972 subjects. Genetic association estimates for cIMT and carotid plaque were obtained using data from 71,128 and 48,434 participants respectively, whilst estimates for VTE were obtained using data from a study incorporating 7,507 cases and 52,632 controls. Conventional two-sample summary data MR was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of VTE. Odds ratios (ORs) per standard deviation increase in biomarker levels were 1.37 (95% confidence interval 1.14–1.66) for serum iron, 1.25 (1.09–1.43) for transferrin saturation, 1.92 (1.28–2.88) for ferritin, and 0.76 (0.63–0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding ORs were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80–1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no MR evidence of an effect of iron status on cIMT. Conclusions: These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease, but increases risk of thrombosis related to stasis of blood