Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis

Gemmati, Donato; Zeri, G; Orioli, Elisa; Gaetano, Francesca E De; Salvi, Fabrizio; Bartolomei, Ilaria; D’Alfonso, Sandra; Dall’Osso, Claudia; Leone, Maurizio; Singh, Ajay Vikram; Asselta, Rosanna; Zamboni, Paolo

doi:10.1186/1471-2350-13-70

Cited by 42 publications

(36 citation statements)

References 57 publications

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“…Rubio et al ( Rubio et al, 2004 ) reported an increased frequency of the HFE C282Y mutation in MS compared to HC (10.2% vs. 6.7%). A more recent study investigating the association of iron related polymorphisms in MS found an increased Multiple Sclerosis Severity Score (MSSS) and disease progression in H63D-, but not among C282Y- carriers ( Gemmati et al, 2012 ). Presence of any iron risk polymorphism under investigation (H63D, C282Y, and others vs. wild-type) was associated with higher EDSS, MSSS, and progression scores.…”

Section: Discussionmentioning

confidence: 99%

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals

Hagemeier

Ramanathan

Schweser

et al. 2018

NeuroImage: Clinical

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Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE: rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: − 5.3 ppb, right: − 6.7 ppb, p < 0.05). Female MS patients had lower susceptibility in the caudate (− 6.0 ppb) and putamen (left: − 3.9 ppb, right: − 4.6 ppb) than men, but only when they had a wild-type allele (p < 0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

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Section: Discussionmentioning

confidence: 99%

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals

Hagemeier

Ramanathan

Schweser

et al. 2018

NeuroImage: Clinical

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“…Polymorphisms in genes encoding iron-binding and iron-transporting proteins are associated with disability, disease severity and early progression in MS 26 . Rithidech et al .…”

Section: Discussionmentioning

confidence: 99%

Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis

Lewin¹,

Hamilton²,

Witkover³

et al. 2016

Wellcome Open Res

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A major cause of disability in secondary progressive multiple Background sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS.: We used surface-enhanced laser desorption-ionization time-of-flight Methods mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS. Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry.: There was a significant (p<0.004) correlation between the rate of Results brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta-haemoglobin, respectively. The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001). The serum lactate dehydrogenase activity was also highly significantly raised (p<10 ) in patients with secondary progressive multiple sclerosis.: The results are consistent with the following hypothesis. In Conclusions progressive multiple sclerosis, low-grade chronic intravascular haemolysis releases haemoglobin into the serum; the haemoglobin is subsequently translocated into the central nervous system (CNS) across the damaged blood-brain barrier. In the CNS, the haemoglobin and its breakdown products, including haem and iron, contribute to the neurodegeneration and consequent brain atrophy seen in progressive disease. We postulate that haemoglobin is a source of the iron whose deposition along blood vessels in multiple sclerosis plaques is associated with neurodegeneration. Amendments from Version 1We thank the reviewers for their comments and suggestions. In the revised version of the paper (v.2), we have taken into account the points raised by each set of reviewers. The main changes are the following:-clarification of points of methodology (e.g. sampling; use of Top 12 protein depletion columns) -more cautious wording on possible therapy, and to make clear the principle that we have not proved causality or claim that free serum haemoglobin is the sole correlate of brain atrophy in SPMS -clearer and fairer representation of the results reported in previous publications -addition of 8 papers to the bibliography, citing -as suggested -both old work (on erythrocyte fragility) and very recent work -answering specific points concerning the normal total blood haemoglobin concentration and the kinetics of neurodegeneration -significance values for pairwise statistical tests in Figure 3.

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“…Several groups reported on the genetic polymorphism of the proteins involved in iron homeostasis, but not related to iron deficiency or overload [116,117,118]. Genetic analysis of iron deficiency in mice has been evaluated [119].…”

Section: Genetic Polymorphism Of Proteins Involved In Iron Metabolismmentioning

confidence: 99%

Physiology of Iron Metabolism

Waldvogel-Abramowski

Waeber²,

Gassner³

et al. 2014

Transfus Med Hemother

208

146

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A revolution occurred during the last decade in the comprehension of the physiology as well as in the physiopathology of iron metabolism. The purpose of this review is to summarize the recent knowledge that has accumulated, allowing a better comprehension of the mechanisms implicated in iron homeostasis. Iron metabolism is very fine tuned. The free molecule is very toxic; therefore, complex regulatory mechanisms have been developed in mammalian to insure adequate intestinal absorption, transportation, utilization, and elimination. ‘Ironomics' certainly will be the future of the understanding of genes as well as of the protein-protein interactions involved in iron metabolism.

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Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis

Cited by 42 publications

References 57 publications

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals

Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis

Physiology of Iron Metabolism

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