Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission.
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 epitopes.


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 transcriptomic 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: TGFbeta1, CD58 and DBC1. TGFbeta1 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 putative 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.


CONCLUSIONS
The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.
Arthur
Ariel T
AT
Department of Medicine and the Nerve Research Foundation, the University of Sydney, Sydney, Australia. ariela@med.usyd.edu.au
Armati
Patricia J
PJ
Bye
Chris
C
Heard
Robert N S
RN
Stewart
Graeme J
GJ
Pollard
John D
JD
Booth
David R
DR
D000328:Adult; D000368:Aged; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D005819:Genetic Markers; D053773:Transforming Growth Factor beta1; D001094:Arachidonate 5-Lipoxygenase