Genetically Predicted Iron Status and Cardiovascular Function and Structure: A Mendelian Randomization Study

Iron levels imbalances are linked to cardiovascular outcomes. We aimed to assess the association between genetically predicted lifelong higher iron levels and cardiovascular outcomes, employing a two-sample Mendelian randomization (MR) approach to account for confounding biases. We used a study involving 257,953 subjects across six cohort studies that identified genetic variants consistently associated with iron biomarkers, including ferritin, serum iron, total iron binding capacity (TIBC), and transferrin saturation (TSAT). The UK Biobank study was used to investigate the association between the same genetic variants and left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), left ventricular mass (LVM) and left ventricular mass-to-end-diastolic volume ratio (LVMVR). Two-sample MR approach was used in our main analysis. Heterogeneity, pleiotropy, bidirectional MR, MR-Egger, weighted median, and weighted mode were explored in the sensitivity analysis. One standard deviation (SD) increase in genetically predicted serum iron levels was associated with lower LVEDV (beta (95%CI): -0.11, (-0.19, -0.03), p-value=0.006) and lower LVESV (-0.11 (-0.19, -0.03), p-value=0.007). Moreover, one SD increase in genetically predicted TSAT was associated with higher LVMVR (0.09, (0.03, 0.15), p-value=0.005). Heterogeneity, pleiotropy, and bidirectional effects were not observed. The identified associations were explained by HFE, TMPRSS6, TF and TFR2 genes. No other associations were identified between iron biomarkers and cardiovascular outcomes. Our study provides MR evidence that both lower and higher iron status may alter cardiovascular function and structure. HFE, TMPRSS6, TF and TFR2 genes play a crucial role in the identified associations.