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BMC Genet. 2015 Jul 11;16:79. doi: 10.1186/s12863-015-0246-4.

Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?

Author information

1
Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. tessel.galesloot@radboudumc.nl.
2
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. ljanss@icloud.com.
3
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. sb452@medschl.cam.ac.uk.
4
Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Bart.Kiemeney@radboudumc.nl.
5
Department of Internal Medicine, VU Medical Centre, Amsterdam, The Netherlands. m.denheijer@vumc.nl.
6
Department of General Internal Medicine, Division of Vascular Medicine, Radboud university medical center, Nijmegen, The Netherlands. Jacqueline.deGraaf@radboudumc.nl.
7
Department of General Internal Medicine, Division of Vascular Medicine, Radboud university medical center, Nijmegen, The Netherlands. s.holewijn@upcmail.nl.
8
Research Vascular Center Rijnstate, Arnhem, The Netherlands. s.holewijn@upcmail.nl.
9
The University of Queensland, Queensland Brain Institute, St Lucia, Queensland, 4072, Australia. b.benyamin@uq.edu.au.
10
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4029, Australia. b.benyamin@uq.edu.au.
11
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4029, Australia. John.Whitfield@qimrberghofer.edu.au.
12
Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Dorine.Swinkels@radboudumc.nl.
13
Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. sita.vermeulen@radboudumc.nl.

Abstract

BACKGROUND:

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.

RESULTS:

Analyses 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.

CONCLUSIONS:

Our 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.

PMID:
26159428
PMCID:
PMC4498499
DOI:
10.1186/s12863-015-0246-4
[Indexed for MEDLINE]
Free PMC Article

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