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

BMC Medical Genetics

Research Article

Donato Gemmati¹  Giulia Zeri¹  Elisa Orioli¹  Francesca E De Gaetano¹  Sandra D’Alfonso²  Ilaria Bartolomei³  Fabrizio Salvi³  Ajay V Singh⁴  Rosanna Asselta⁵  Claudia Dall’Osso⁶  Maurizio A Leone⁷  Paolo Zamboni⁸ 

[1] Department of Biomedical Sciences & Advanced Therapies, Hematology Unit - Center Hemostasis & Thrombosis, University of Ferrara, Ferrara, Italy;Department of Medical Sciences and IRCAD, Eastern Piedmont University, Novara, Italy;Department of Neurology, Bellaria Hospital, Bologna, Italy;Department of Physics, European School of Molecular Medicine (SEMM), University of Milan, Milan, Italy;Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy;Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy;Stem Cell and Regenerative Biology (SCRB) Department, Harvard University, 02138, Cambridge, MA, USA;SCDU Neurologia, Ospedale Maggiore della Carità and IRCAD, Novara, Italy;Vascular Diseases Center, University of Ferrara, Ferrara, Italy;

关键词: Multiple Sclerosis;    Multiple Sclerosis Patient;    Expand Disability Status Scale;    Multiple Sclerosis Group;    Multiple Sclerosis Case;   

DOI  :  10.1186/1471-2350-13-70

 received in 2011-09-09, accepted in 2012-07-30,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundIron 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.MethodsBy 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).ResultsThe 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).ConclusionsPolymorphisms 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.

【 授权许可】

CC BY   
© Gemmati et al.; licensee BioMed Central Ltd. 2012