A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex

Abstract

Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s).

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

“…Although the association of HLA class II alleles with multiple sclerosis is readily demonstrated, 8,24 the effect of this locus on susceptibility is modest and therefore evidence for linkage in this region is expected to be difficult to confirm. Previous linkage screens in out-bred populations of northern European origin (American, British and Canadian) [12][13][14] showed only modest evidence for linkage to the HLA region. Our study is in keeping with these results in that it also shows only modest evidence for linkage in the HLA-region on chromosome 6p21.…”

“…Genes and Immunity age screen in multiple sclerosis 13 and one in a genomewide screen for linkage in rheumatoid arthritis. 29 The region on the short arm of chromosome 16 coincides with one of the best supported non-HLA regions from the recently published meta-analysis of the original American, British and Canadian linkage screens in multiple sclerosis.…”

“…11 In multiple sclerosis, six whole genome screens for linkage have now been performed. [12][13][14][15][16][17] No one has shown unequivocal linkage, but most have identified more regions of potential linkage than expected by chance and together they provide the best available summary of the likely location of the relevant genes. 18 The high prevalence of multiple sclerosis (120/100 000) in Scandinavia 19 and the striking correlation between its global geographical distribution and the migration pattern of northern Europeans 20 suggest that important susceptibility alleles may have arisen in Scandinavia and been disseminated by their descendants-the so-called 'Viking hypothesis'.…”

Intercellular adhesion molecule-1: a protective haplotype against multiple sclerosis

“…34,35 Previous studies have addressed the role of ICAM-1 in MS genetics with conflicting results. One study, performed on case-controls of Polish origin, found a genetic association with ICAM-1 K469.…”

Single nucleotide polymorphisms in MHC2TA, the gene encoding the MHC class II transactivator (CIITA)

“…2 The human CIITA gene, MHC2TA, which spans 42 kb, 4 was mapped to chromosome 16p13, 1 a region linked to multiple sclerosis (MS) susceptibility. 5,6 Given its pivotal role in MHC class II regulation, MHC2TA is also considered an important candidate gene in other autoimmune diseases. 7 In order to investigate the potential association of MHC2TA with autoimmune diseases, we have first examined the coding region and promoter elements in normal individuals for polymorphisms and established the allele frequencies of identified SNPs.…”