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

Galesloot, Tessel E, Janss, Luc L, Burgess, Stephen, Kiemeney, Lambertus A.L.M, den Heijer, Martin, de Graaf, Jacqueline, Holewijn, Suzanne, Benyamin, Beben, Whitfield, John B, Swinkels, Dorine W and Vermeulen, Sita H (2015) Iron and hepcidin as risk factors in atherosclerosis: What do the genes say?. BMC Genetics, 16 79: . doi:10.1186/s12863-015-0246-4

Author Galesloot, Tessel E
Janss, Luc L
Burgess, Stephen
Kiemeney, Lambertus A.L.M
den Heijer, Martin
de Graaf, Jacqueline
Holewijn, Suzanne
Benyamin, Beben
Whitfield, John B
Swinkels, Dorine W
Vermeulen, Sita H
Title Iron and hepcidin as risk factors in atherosclerosis: What do the genes say?
Journal name BMC Genetics   Check publisher's open access policy
ISSN 1471-2156
Publication date 2015-07-11
Year available 2015
Sub-type Article (original research)
DOI 10.1186/s12863-015-0246-4
Open Access Status DOI
Volume 16
Issue 79
Total pages 12
Publisher BioMed Central
Collection year 2016
Language eng
Formatted 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.
Keyword Hepcidin
Cardiovascular diseaseHepcidin
General population
Mendelian randomization
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
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