Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
Intracellular adhesion molecule-1 (ICAM-1) plays an important role in the cascade of adhesion events in the homing of inflammatory cells to the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Two single-base ICAM-1 polymorphisms have been described, in exons 4 and 6, changing codons 241 and 469 in the ICAM-1 gene, respectively. Both polymorphisms result in amino acid changes and can potentially lead to different interactions of ICAM-1 with its ligands. To detect ICAM-1 gene polymorphisms in MS, we have developed a highly sensitive and site-specific, two-stage, nested polymerase chain reaction. Genomic DNA was extracted from blood cells of 79 MS patients and 68 control subjects. The results were confirmed by direct dideoxy chain termination sequencing. The frequency of exon 6 allele T was found to be significantly higher in MS patients than in controls (68% vs 49%). Most interesting, the frequency of exon 6 homozygote K469 was significantly higher in MS patients than in controls (53% vs 34%). Higher frequency of the K469 genotype was found to be independent of possible linkage with the previously described MS susceptibility factor, the HLA class I1 DR2 allele. In the present study, we have shown for the first time the ICAM-1 gene polymorphisms in MS. The results indicate increased frequency of ICAM-1 exon 6 allele T in MS patients, which may contribute to the MS genetics background. According to structural similarities, adhesion molecules are divided into the selectins, the integrin and the Ig superfamilies, the addressins, the cadherins, and the CD44.6 During the T cell-EC interactions, the selectins are responsible for early contact and for lymphocyte "rolling" along the blood vessels.' The subsequent, firm adhesion event is mediated by the integrins expressed on activated leukocytes and Ig-like adhesion molecules expressed on ECs8 The Ig superfamily contains intercellular adhesion molecules (ICAMs), ie, ICAM-1, ICAM-2, and ICAM-3, vascular cellular adhesion molecule-1 (VCAM-I), and leukocyte functionassociated antigen-3 (LFA-3).' ICAM-1 expression was shown to be significantly up-regulated by treating brain ECs with Thl-type cytokines, ie, interferon-?, interleukin-1 a, and tumor necrosis factor, which have been shown to be involved in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). 13,14 ICAM-1 interacts with leukocyte function-associated antigen-1 (LFA-1) and with another p2 integrin, Mac-l.'-'In MS and EAE it has been shown that most important in T-cell transendothelial migration are interactions of LFA-1 with ICAM-1 and of very late activation antigen-4 (VLA-4) with 5,15 Increased levels of soluble ICAM-1 have been detected in blood from MS patients, the levels tend to rise in association with the disease clinical and magnetic resonance imaging (MRI) activities.'".'' In actively induced EAE, anti-ICAM-1 antibody injections reduced the severity of clinical signs and pathological changes.I8 Moreov...
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