Effects of Genetically Determined Iron Status on Risk of Venous Thromboembolism and Carotid Atherosclerotic Disease: A Mendelian Randomization Study

Abstract

Background Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this study was to investigate the effect of genetically determined iron status on carotid intima‐media thickness, carotid plaque, and venous thromboembolism using Mendelian randomization. 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 carotid intima‐media thickness and carotid plaque were obtained using data from 71 128 and 48 434 participants, respectively, and estimates for venous thromboembolism were obtained using data from a study incorporating 7507 cases and 52 632 controls. Conventional 2‐sample summary data Mendelian randomization was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of venous thromboembolism. Odds ratios per SD increase in biomarker levels were 1.37 (95% CI 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 odds ratios 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 Mendelian randomization evidence of an effect of iron status on carotid intima‐media thickness. Conclusions These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease but increases the risk of thrombosis related to stasis of blood.

Hematocrit and incidence of venous thromboembolism

“…This raises the possibility that hemoglobin and hematocrit may reflect disordered iron metabolism, which may contribute to increased VTE risk. Several studies support this hypothesis; for example, a recent Mendelian randomization study showed that a higher genetically determined iron status may increase risk of VTE . Likewise, analysis from the Tromsø Study recently reported that higher plasma hepcidin was associated with increased VTE incidence .…”

“…Several studies support this hypothesis; for example, a recent Mendelian randomization study showed that a higher genetically determined iron status may increase risk of VTE. 25 Likewise, analysis from the Tromsø Study recently reported that higher plasma hepcidin was associated with increased VTE incidence. 26 Hepcidin is a key iron-regulatory hormone and an acute phase inflammatory biomarker that is increased in anemia of chronic disease.…”

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

“…Some epidemiological studies found that blood iron is lower in hyperlipidemic patients [ 42 ] and that blood ferritin is negatively associated with LDL cholesterol [ 13 ]. Very likely related, elevated iron status is negatively associated with coronary artery disease in both observational and MR studies [ 43 , 44 ]. Other studies have found that anemic and/or iron-deficient patients and animal models tend to have lower blood TC and LDL cholesterol [ 45 ], while blood ferritin has often been found to be positively associated with an unhealthy lipid profile (i.e., elevated TC, LDL cholesterol, and triglyceride, but decreased HDL cholesterol) [ 46 ].…”

Iron Status and Cancer Risk in UK Biobank: A Two-Sample Mendelian Randomization Study

“…In a GWAS consisting of 48,972 individuals of European ancestry, the Genetics of Iron Status Consortium identified five single nucleotide polymorphisms (SNP) associated with serum iron and transferrin saturation, six SNPs associated with ferritin and eight SNPs associated with transferrin at the genome-wide significance threshold (p < 5 × 10 −8 ) [13] (Table 1). Among those SNPs, three SNPs (rs1800562 and rs1799945 in HFE and rs855791 in TMPRSS6) showed a robust and consistent association with a systemic iron status and explained the majority of variance for each iron status biomarker [14] and have been used as instrumental variables for iron status in previous MR studies [14][15][16]. The SNPs were uncorrelated (R 2 < 0.01) and explained 3.4%, 7.2%, 6.9% and 0.9% of the variance for serum iron, transferrin, transferrin saturation and ferritin levels, respectively [13].…”