• Dipender Gill, Fabiola Del Greco M, Ann P Walker, Surjit K S Srai, Michael A Laffan, and Cosetta Minelli.
• From the Imperial College Healthcare NHS Trust, London, United Kingdom (D.G., M.A.L.); Department of Clinical Pharmacology and Therapeutics (D.G.), Department of Haematology (M.A.L.), and Department of Population Health and Occupational Disease (C.M.), Imperial College London, United Kingdom; Institute for Biomedicine, Eurac Research, Bolzano, Italy (F.D.G.M.); and Centre for Cardiovascular Genetics (A.P.W.), and Division of Biosciences (S.K.S.S.), University College London, United Kingdom. dipender.gill@imperial.ac.uk.
• Arterioscler. Thromb. Vasc. Biol. 2017 Sep 1; 37 (9): 1788-1792.

ObjectiveIron status is a modifiable trait that has been implicated in cardiovascular disease. This study uses the Mendelian randomization technique to investigate whether there is any causal effect of iron status on risk of coronary artery disease (CAD).Approach And ResultsA 2-sample Mendelian randomization approach is used to estimate the effect of iron status on CAD risk. Three loci (rs1800562 and rs1799945 in the HFE gene and rs855791 in TMPRSS6) that are each associated with serum iron, transferrin saturation, ferritin, and transferrin in a pattern suggestive of an association with systemic iron status are used as instruments. SNP (single-nucleotide polymorphism)-iron status association estimates are based on a genome-wide association study meta-analysis of 48 972 individuals. SNP-CAD estimates are derived by combining the results of a genome-wide association study meta-analysis of 60 801 CAD cases and 123 504 controls with those of a meta-analysis of 63 746 CAD cases and 130 681 controls obtained from Metabochip and genome-wide association studies. Combined Mendelian randomization estimates are obtained for each marker by pooling results across the 3 instruments. We find evidence of a protective effect of higher iron status on CAD risk (iron odds ratio, 0.94 per SD unit increase; 95% confidence interval, 0.88-1.00; P=0.039; transferrin saturation odds ratio, 0.95 per SD unit increase; 95% confidence interval, 0.91-0.99; P=0.027; log-transformed ferritin odds ratio, 0.85 per SD unit increase; 95% confidence interval, 0.73-0.98; P=0.024; and transferrin odds ratio, 1.08 per SD unit increase; 95% confidence interval, 1.01-1.16; P=0.034).ConclusionsThis Mendelian randomization study supports the hypothesis that higher iron status reduces CAD risk. These findings may highlight a therapeutic target.© 2017 American Heart Association, Inc.

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