P6231Iron status and risk of cardio-metabolic diseases in European adults: a Mendelian randomization study

Abstract

Abstract Background Observational studies have reported conflicting results about the associations of iron status with risk of cardio-metabolic diseases but such studies are constrained by confounding and reverse causality. Purpose To assess the causal relevance of iron status biomarkers (transferrin, serum iron, and ferritin) for risk of coronary artery diseases (CAD), ischaemic stroke (IS), and type 2 diabetes (T2D), using Mendelian randomization (MR). Methods Effect size estimates for genetic variants associated with iron status biomarkers were obtained from the Genetics of Iron Status consortium (transferrin saturation, serum iron, and ferritin: n=48,972). The corresponding effects of these variants on the risk of CAD, IS and T2D were obtained from a meta-analysis of unrelated participants of European ancestry in the UK Biobank (UKB), together with previously recruited participants in CARDIOGRAMplusC4D (total n=90,377 CAD cases), MEGASTROKE (total n=43,381 IS cases) and DIAGRAM (total n=74,124 T2D cases), respectively. The main analysis used a two-sample inverse-variance weighted MR, while the sensitivity analyses used weighted-median, weighted-mode, MR-PRESSO, and MR-Egger approaches. Results MR analysis demonstrated significant inverse association of each of the three genetically-instrumented iron status biomarker with risk of CAD (transferrin saturation OR=0.96 [95% CI: 0.92–0.99], p=0.02; serum iron OR=0.93 [0.89–0.97], p=0.001; and ferritin OR=0.86 (0.79–0.94), p=0.001, per 1 SD higher level). In contrast, these iron status biomarkers showed positive associations with risk of T2D (transferrin saturation OR=1.06 [1.01–1.11], p=0.01; serum iron OR=1.06 [0.99–1.13], p=0.07; and ferritin OR=1.12 [0.99–1.26], p=0.06, per 1 SD higher level). There was positive, but non-significant, association of IS with each of the iron status biomarker analysed. Sensitivity analyses using several different MR approaches yielded concordant results. Conclusions Among European adults, iron status appeared to have causal associations, but in opposite directions, with the risk of CHD and T2D. Our findings highlight the need for caution about strategies for advocating iron supplementation in individuals with normal haemoglobin levels for prevention of CAD. Acknowledgement/Funding British Heart Found, Medical Research Council, Wellcome Trust, NIHR Biomedical Research Centre, Oxford