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An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus

DeLuca, Gabriele C. and Ramagopalan, Sreeram V. and Herrera, Blanca M. and Dyment, David Alexandre and Lincoln, Matthew R. and Montpetit, Alexandre and Pugliatti, Maura and Barnardo, Martin C. N. and Risch, Neil J. and Sadovnick, A. Dessa and Chao, Michael and Sotgiu, Stefano and Hudson, Thomas J. and Ebers, George C. (2007) An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proceedings of The National Academy of Sciences, Vol. 104 (52), p. 20896-20901. eISSN 1091-6490. Article.

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DOI: 10.1073/pnas.0707731105

Abstract

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n=63), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.

Item Type:Article
ID Code:1142
Status:Published
Refereed:Yes
Uncontrolled Keywords:Multiple sclerosis, HLA-DRB1 locus, alleles, neurologia
Subjects:Area 06 - Scienze mediche > MED/26 Neurologia
Divisions:001 Università di Sassari > 03 Istituti > Clinica neurologica
Publisher:The National Academy of Sciences of the USA
eISSN:1091-6490
Publisher Policy:Depositato per gentile concessione dell'Editore. È vietato duplicare e postare il PDF. E' consentito l'uso a solo scopo di studio e di ricerca.
Deposited On:18 Aug 2009 10:04

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