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Pathogenesis of Multiple Sclerosis

Genetics

In the past few years, our understanding of the genetic underpinnings of MS has exploded due to the advent of large genome-wide association studies (GWAS). Clustering within families is a well-known phenomenon. Prior to the recent advances, it was found that in a large MS database in Vancouver and our large database in South Florida, a 20% familial incidence was present in both data sets. The Canadian twin study shows a concordance of 31%, similar to other twin studies [98]. Mothers confer a 20-40 times increased risk to their children, greater for girls than boys. Other first-degree relatives also have a much-increased risk of MS [99].

As of press time, more than 159 genetic variants have been associated with an increased risk of developing MS [100, 101]. For several decades, the major histocompatibility (MHC) gene locus located on chromosome 6 has been implicated, and it is clear that the HLA-DRB1 gene in the class II region of the MHC explains up to 10.5% of the genetic variance underlying risk of MS. A monumental linkage study, conducted by the International Multiple Sclerosis Consortium, evaluated 730 families with multiple cases of MS, further emphasized the role of the major histocompatibility (MHC) class II HLA-DRB1*15:01 allele, as the only variant of several genetic loci to achieve statistical significance [102]. Mouse studies also implicate a strong genetic susceptibility for experimental allergic encephalomyelitis (EAE) localized to the region of DQBq*602 [103]. The more complete characterization of MHC contribution to MS and identification of variants outside the MHC region were not appreciated until the advent of the era of GWAS. Using large

Biopsy of a large left frontal lobe plaque from a 29-year-old woman with new onset multiple sclerosis with recurrent right hemiparesis over 3 months and new mild speech difficulty

Fig. 2.3 Biopsy of a large left frontal lobe plaque from a 29-year-old woman with new onset multiple sclerosis with recurrent right hemiparesis over 3 months and new mild speech difficulty. (a) Specimen is stained with Luxol fast blue counterstained with eosin. A new active plaque is shown which is not sharply demarcated but exhibits prominent perivascular cellulaiity with varying myelin damage and relative sparing of axons. The inflammatory infiltrate is composed of lymphocytes (predominantly CD4 Thj cells) and a large number of macrophages. These cells are predominantly of hematogenous origin and are considered the perpetrators of tissue damage. These features are in contrast to chronic or inactive plaques which exhibit relatively few or no inflammatory cells but contain prominent myelin damage and gliosis. Axonal loss may be prominent. (b) Frontal lobe biopsy: Luxol fast blue counterstained with eosin. Higher power view showing loss of axons and more prominent myelin loss. Note that axons that are preserved exhibit variable loss of myelin sample sizes, the largest of which numbered 80,095 subjects, this technique identified 110 non-MHC risk variants in 103 loci. Interestingly, 78% of predicted MS heritability remains undetermined [104]. Improving whole-genome sequencing technologies hold promise to identify rare genetic variants.

A limited number of causative gene variants have been identified. The MS-associated SNP rs6897932, located in the alternatively spliced exon 6 of IL-7Ra, alters the ratio between the soluble and membrane-bound isoforms of the protein by disrupting an exonic splicing enhancer [105]. The risk variant rs1800693 in the tumor necrosis factor (TNF) 1A gene that drives the expression of a novel soluble form of the receptor that can inhibit TNF signaling mimics the effects of TNF-blocking drugs that are known to exacerbate MS pathology [106]. Other variants include rs3453644, acting at the tyrosine kinase 2 protein, and rs12487066 associated with decreased levels of human endogenous retrovirus Casitas B-lineage lymphoma proto-oncogene B in CD4+ T cells [107, 108]. The underlying pathogenic mechanisms for these variants remain unclear. The current collaborative studies arose from early findings by Jersild et al. who found that the alleles A3, B7, and DR2 [109] occurred twice as commonly in MS as compared with the unaffected population. They observed that in patients that possessed both HLA-B7 and DR2, that disease was particularly severe [109]. Many genes important in normal immune function and in immune-mediated tissue damage, such as tumor necrosis factor, are located in the region between HLA-B7 and the DR locus. Several mutations of genes resident in this area are currently being studied. An important study looking for single nucleotide polymorphisms (SNP), modeled on the Crohn’s disease study, is currently under way as part of the human genome project. As yet there is no single gene, or combination of genes, implicated in the risk or causation of MS.

Once disease-causing gene variants are identified, the next step is to identify biomarkers that can predict disease progression. Our understanding of the factors leading to neurodegeneration and increased disability in progressive MS remains limited, and genetics may shed significant light on this process.

Several reports have described familial clustering of MS phenotype. The presence of the HLA-B*44 allele is thought to be associated with better neuroimaging outcomes [110]. Variants associated with age of onset and a range of radiologic outlooks include HLA-DRB1*15:01, HLA-DRB1*07:01 and HLA-DRB1*11:04, and HLA-DRB1*01:03 [111-114]. The absence of HLA-B5 independently associates with a marked increase in the severity of MS, as in the Afro-American population [110]. Future directions for pharmacogenetics research in MS include identification of specific genetic variants associated with treatment response, leading to a tailored therapy approach. SNP genotype data led to the discovery of several HLA genes and may be used to identify IFN-p super-responders. An important recent study found an association between the rs9828519 variants, which is intronic to SLC9A9 and implicated as a regulator of proinflammatory lymphocyte activation and MS disease response and nonresponse to IFN-p [115, 116].

Studies of migrant populations have suggested the presence of an environmental factor. Although generally interpreted as evidence that a viral infection is playing a role in multiple sclerosis, no conclusive evidence of a specific virus playing a role in multiple sclerosis has been produced [11, 71, 117, 118].

 
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