Abstract
Background: Observational studies produced inconsistent results of the association between iron status and cardiovascular diseases. Previous Mendelian randomization (MR) study prompted a protective effect of iron status in coronary heart disease. Aims: Using genetic instrumental variables, we evaluated how the risk of non-ischemic cardiomyopathy and its different phenotypes are affected by genetically predicted systemic iron status. Methods: Two-sample MR analyses were performed to estimate the causal effect of four biomarkers of systemic iron status on diagnosed cardiomyopathy and its subtypes in 242,607 participants from the FinnGen research project. Inverse-weighted method and multiple sensitivity analysis were conducted to confirm the results. Results: The level of transferrin saturation was significantly associated with an increased risk of cardiomyopathy (OR per SD, 1.17; 95% CI, 1.13-1.38) when using nine separately selected genetic instruments. Conservative estimates were obtained by pooling results across four mutual genetic variants (rs1800562, rs1799945, rs855791 and rs57659670). Accordingly, genetically determined serum iron (OR, 1.25; 95% CI, 1.13-1.38), ferritin (OR, 1.49; 95% CI, 1.02-2.18) and transferrin saturation (OR, 1.21; 95% CI, 1.04-1.39) were positively associated with cardiomyopathy risk, while total iron binding capacity, a marker of reduced iron status, was protective (OR, 0.80; 95% CI, 0.65-0.98). The risk effect of iron status was more evident in hypertrophic cardiomyopathy and related heart failure. Red blood cell traits, blood pressure and blood lipids were not mediated in the causal effect. Results were robust in all sensitivity analyses. Conclusions: These analyses support a causal effect of increased systemic iron status on higher risk of non-ischemic cardiomyopathy. Modulation of iron status may, therefore, directly influence cardiomyopathy risk.
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