Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission
Arthur, AT and Armati, PJ and Bye, C and Kilpatrick, TJ and Foote, SJ and Butzkueven, H and Taylor, BV and Tubridy, N and Marriott, M and Chapman, C and Bahlo, M and Speed, TP and Stankovich, J (2008) Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission. BMC Medical Genetics, 9 (Mar 19). pp. 17-29. ISSN 1471-2350
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Official URL: http://dx.doi.org/10.1186/1471-2350-9-17
Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous
system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune
disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte
Methods: In this study we investigated the gene expression profiles of peripheral blood cells from patients
with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated
genes encoded in regions associated with MS susceptibility from genomic screens or previous
trancriptomic studies were identified. The proximal promoter region polymorphisms of two genes were
tested for association with disease and expression level.
Results: Distinct sets of dysregulated genes during the relapse and remission phases were identified
including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been
previously implicated with MS susceptibility in genomic screens: TGFβ1, CD58 and DBC1. TGFβ1 has one
common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets
(total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13).
Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting
regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found
over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putatve promoter: -
557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and
-176; but no evidence for transmission distortion found.
Conclusion: The dysregulation of these genes tags their metabolic pathways for further investigation for
potential therapeutic intervention.
|Additional Information:||© 2008 Arthur et al; licensee BioMed Central Ltd.|
|Deposited By:||Ms Emma Stubbs|
|Deposited On:||18 Dec 2008 12:37|
|Last Modified:||18 Dec 2008 12:37|
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