Appraising the Causal Association between Systemic Iron Status and Heart Failure Risk: A Mendelian Randomisation Study

Abstract

Although observational studies have shown that abnormal systemic iron status is associated with an increased risk of heart failure (HF), it remains unclear whether this relationship represents true causality. We aimed to explore the causal relationship between iron status and HF risk. Two-sample Mendelian randomisation (MR) was applied to obtain a causal estimate. Genetic summary statistical data for the associations (p < 5 × 10−8) between single nucleotide polymorphisms (SNPs) and four iron status parameters were obtained from the Genetics of Iron Status Consortium in genome-wide association studies involving 48,972 subjects. Statistical data on the association of SNPs with HF were extracted from the UK biobank consortium (including 1088 HF cases and 360,106 controls). The results were further tested using MR based on the Bayesian model averaging (MR-BMA) and multivariate MR (MVMR). Of the twelve SNPs considered to be valid instrumental variables, three SNPs (rs1800562, rs855791, and rs1799945) were associated with all four iron biomarkers. Genetically predicted iron status biomarkers were not causally associated with HF risk (all p > 0.05). Sensitivity analysis did not show evidence of potential heterogeneity and horizontal pleiotropy. Convincing evidence to support a causal relationship between iron status and HF risk was not found. The strong relationship between abnormal iron status and HF risk may be explained by an indirect mechanism.

Keywords: Mendelian randomisation; causal association; heart failure; iron status.

Figure 1

Schematic diagram of the Mendelian randomisation study design. (a) Two-sample Mendelian randomisation (TSMR). (b) Multivariate Mendelian randomisation (MVMR).

Figure 2

Flowsheet of Mendelian randomisation in this study. TS—transferrin saturation; BMA—Bayesian model averaging.

Figure 3

Forest plot summarising the overall Mendelian randomisation estimates of SNP specificity and the causal effect on heart failure. (a) Using three SNPs associated with all four iron biomarkers; (b) using separately selected SNPs associated with each iron status biomarker. OR—odds ratio; CI—confidence interval.

Figure 4

Leave-one-out analysis of the causal association between iron status and heart failure risk. (a–d) Using three SNPs associated with all four iron biomarkers; (e–h) using separately selected SNPs associated with each iron status biomarker.