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Open Access Highly Accessed Research article

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

Donato Gemmati1*, Giulia Zeri1, Elisa Orioli1, Francesca E De Gaetano1, Fabrizio Salvi2, Ilaria Bartolomei2, Sandra D’Alfonso3, Claudia Dall’Osso45, Maurizio A Leone6, Ajay V Singh7, Rosanna Asselta4 and Paolo Zamboni8

Author Affiliations

1 Department of Biomedical Sciences & Advanced Therapies, Hematology Unit - Center Hemostasis & Thrombosis, University of Ferrara, Ferrara, Italy

2 Department of Neurology, Bellaria Hospital, Bologna, Italy

3 Department of Medical Sciences and IRCAD, Eastern Piedmont University, Novara, Italy

4 Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy

5 Stem Cell and Regenerative Biology (SCRB) Department, Harvard University, Cambridge, MA, 02138, USA

6 SCDU Neurologia, Ospedale Maggiore della Carità and IRCAD, Novara, Italy

7 Department of Physics, European School of Molecular Medicine (SEMM), University of Milan, Milan, Italy

8 Vascular Diseases Center, University of Ferrara, Ferrara, Italy

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BMC Medical Genetics 2012, 13:70  doi:10.1186/1471-2350-13-70

Published: 10 August 2012

Abstract

Background

Iron involvement/imbalance is strongly suspected in multiple sclerosis (MS) etiopathogenesis, but its role is quite debated. Iron deposits encircle the veins in brain MS lesions, increasing local metal concentrations in brain parenchyma as documented by magnetic resonance imaging and histochemical studies. Conversely, systemic iron overload is not always observed. We explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes in MS patients.

Methods

By the pyrosequencing technique, we investigated 414 MS cases [Relapsing-remitting (RR), n=273; Progressive, n=141, of which: Secondary (SP), n=103 and Primary (PP), n=38], and 414 matched healthy controls. Five SNPs in 4 genes were assessed: hemochromatosis (HFE: C282Y, H63D), ferroportin (FPN1: -8CG), hepcidin (HEPC: -582AG), and transferrin (TF: P570S).

Results

The FPN1-8GG genotype was overrepresented in the whole MS population (OR=4.38; 95%CI, 1.89-10.1; P<0.0001) and a similar risk was found among patients with progressive forms. Conversely, the HEPC -582GG genotype was overrepresented only in progressive forms (OR=2.53; 95%CI, 1.34-4.78; P=0.006) so that SP and PP versus RR yielded significant outputs (P=0.009). For almost all SNPs, MS disability score (EDSS), severity score (MSSS), as well as progression index (PI) showed a significant increase when comparing homozygotes versus individuals carrying other genotypes: HEPC -582GG (EDSS, 4.24±2.87 vs 2.78±2.1; P=0.003; MSSS, 5.6±3.06 vs 3.79±2.6; P=0.001); FPN1-8GG (PI, 1.11±2.01 vs 0.6±1.31; P=0.01; MSSS, 5.08±2.98 vs 3.85±2.8; P=0.01); HFE 63DD (PI, 1.63±2.6 vs 0.6±0.86; P=0.009). Finally, HEPC -582G-carriers had a significantly higher chance to switch into the progressive form (HR=3.55; 1.83-6.84; log-rank P=0.00006).

Conclusions

Polymorphisms in the genes coding for iron binding and transporting proteins, in the presence of local iron overload, might be responsible for suboptimal iron handling. This might account for the significant variability peculiar to MS phenotypes, particularly affecting MS risk and progression paving the way for personalized pharmacogenetic applications in the clinical practice.