Abstract
BackgroundPrevious reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis.ResultsAnalyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [−0.27 (SE 0.34) and −0.22 (SE 0.35), respectively] and ABI after exercise [−0.29 (SE 0.34) and −0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations.ConclusionsOur results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0246-4) contains supplementary material, which is available to authorized users.
Highlights
Previous reports suggested a role for iron and hepcidin in atherosclerosis
For the single Single nucleotide polymorphism (SNP) analyses, only the T allele of rs651007, associated with decreased ferritin, showed effects that were consistent with the hypothesized directions of effects for all non-invasive measurements of atherosclerosis (NIMA), with nominal significant effects on intima media thickness (IMT) [beta −0.021] and ankle-brachial index (ABI) after exercise [beta 0.034]
ABI indicates ankle-brachial index, IMT intima media thickness, Standard Error (SE) standard error, total-iron binding capacity (TIBC) total iron-binding capacity, and TS transferrin saturation *Correlations in these rows come from an 8-trait analysis including hepcidin, ferritin, iron, TIBC, presence of plaque, IMT, ABI at rest and ABI after exercise †Correlations in this row come from a 7-trait analysis including the ratio hepcidin/ferritin, iron, TIBC, presence of plaque, IMT, ABI at rest and ABI after exercise ‡Correlations in this row come from a 6-trait analysis including the ratio hepcidin/TS, ferritin, presence of plaque, IMT, ABI at rest and ABI after exercise §Correlations in this row come from a 7-trait analysis including hepcidin, ferritin, TS, presence of plaque, IMT, ABI at rest and ABI after exercise
Summary
Previous reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis. In 1981, the ‘iron hypothesis’ was proposed, stating that iron depletion protects against heart disease [1] According to this hypothesis, premenopausal women have a lower risk of heart disease compared to men and postmenopausal women due to loss of iron with menstruation. In an extension of the ‘iron hypothesis’ in 2007, hepcidin has been hypothesized to increase CVD risk by slowing or preventing the mobilization of iron from macrophages [14], promoting transformation of these cells into foam cells and atherosclerosis [3, 14]. Disentangling the specific causal roles of hepcidin and iron parameters in atherosclerosis and CVD in observational population studies is fraught with difficulties due to potential for residual confounding, reverse causation, and the existing phenotypic correlations between iron parameters and hepcidin
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