Review articleMultiple sclerosis: Genomic rewards
Section snippets
Introduction: multiple sclerosis as a genetic disease
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS) characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction (Hauser and Goodkin, 2001). A large body of data indicates that tissue injury in MS results from an abnormal immune response to one or several myelin antigens occurring in genetically susceptible individuals after exposure to an as yet undefined environmental factor or factors. A genetic
An interplay of genes and environmental factors
Migration studies have been widely used to illustrate potential environmental influences on MS (Kurtzke, 1983, Martyn and Gale, 1997). Children born to parents who have migrated from a high-risk area to a low-risk area for MS appear to have a lower lifetime risk than their parents. Conversely, migration of parents from a low-risk area to a high-risk area may confer a higher risk for MS in the children. Although the interpretation of migration studies has been difficult, in part because the
Population versus family-based studies
The genetic analysis of MS has traditionally focused on population-based association studies of candidate polymorphic genes, in which the frequencies of marker alleles in groups of patients and healthy controls are compared, and the difference is subjected to statistical analysis. The association is often expressed as the relative risk that an individual will develop the disorder if he/she carries the particular allele or marker, compared to an individual who does not carry the allele or
The MHC and multiple sclerosis
The MHC chromosomal region is the strongest and most consistent effect identified in MS, and must be discussed in detail. MHC class I and class II molecules are polymorphic cell surface glycoproteins whose primary role in an immune response is to display and present short antigenic peptide fragments to antigen-specific CD4+ and CD8+ T cells, which can then become activated by a second stimulatory signal and initiate an immune response. In addition, MHC molecules present on stromal cells on the
Susceptibility genes versus modifiers
As summarized above, the MHC locus has consistently demonstrated both association and linkage with MS in case–control and family studies, however the role of a gene within this region in determining clinical features or subtypes of MS is unclear. HLA-DR2 has been reported to be associated with lower age at onset, gender, severe, relapsing-remitting, and mild MS courses, or to have no influence (Celius et al., 2000, Kira et al., 1996, Masterman et al., 2000, McDonnell et al., 1999, Olerup et
Gene expression studies
During the process of lesion formation, lymphocyte activation and recruitment, extravasation, and effector functions involve several cellular phenotypic changes triggered by specific gene expression pathways. Cytokines, adhesion molecules, growth factors, and other molecules, such as free radicals, proteases and vasoactive amines, induce and regulate numerous critical cell functions. The comprehensive analysis of these cellular transcriptional programs, the transcriptome, both in the CNS and
Genetic heterogeneity in MS
Studies with multiplex families confirmed the genetic linkage to the MHC region and the specific association with the HLA-DRB1*1501 allele (MS Genetics Group, 1998). Interestingly, 25% of the families, most of them HLA-DRB1*1501 negative, showed no linkage to the MHC locus. We also detected an increased frequency of the DRB1*1501 susceptibility marker in families with many affecteds compared to families with smaller number of affecteds. Both observations suggest the presence of substantial
A model of inheritance
A simple model of inheritance for all MS is unlikely and cannot account for the nonlinear decrease in disease risk in families with increasing genetic distance from the proband. As summarized above, the available data is most compatible with a complex multifactorial etiology, including both genetic and environmental factors (Table 6). Recurrence risk estimates in multiplex families combined with twin data, predict that the MS-prone genotype results from multiple independent or interacting
Conclusions and future directions
The confluence of recent technological and analytical advances proposes a new experimental view to elucidate the pathogenic mechanisms of this disease. Specifically:
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Groups and consortia with the appropriate experimental, clinical and financial resources will continue the analysis of the MS genome using larger familial DNA datasets and dense and informative genetic markers to further narrow the chromosomal segments harboring disease genes. The potentially critical importance of identifying and
Acknowledgements
The authors are supported by the National Multiple Sclerosis Society, the National Institute of Health, and the Nancy Davis and Sandler Foundations. LFB is a National Multiple Sclerosis Society post-doctoral fellow. The concepts and discussion presented in this paper represent the invaluable continuous interactions with Drs. Jonathan L. Haines (Vanderbilt University), Margaret Pericak-Vance (Duke University) and their colleagues.
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2019, Advances in Medical SciencesCitation Excerpt :The etiology of MS remains elusive, but has been suggested to be affected by both environmental and genetic factors and their complex interaction. A large number of studies suggest a multifactorial etiology on the basis of genetic susceptibility [8]. The human leukocyte antigen (HLA) locus on chromosome 6p21 is an important genetic factor of MS risk [9–11].
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2016, Multiple Sclerosis: A Mechanistic ViewHLA-DRB1 does not have a role in clinical response to interferon-beta among Iranian multiple sclerosis patients
2015, Journal of the Neurological SciencesCitation Excerpt :Despite the recent improvements in our knowledge about genetic role in MS etiology, the role of human leukocyte antigen (HLA) in clinical response to immunotherapy is not completely known. Now it is well understood that alleles of HLA class II on chromosome 6p21 have a great role on genetic susceptibility to MS, particularly HLA-DR and DQ alleles (DRB1*1501, DRB5*0101, DQA1*0102, and DQB1*0602) [1–3,9–11] and among the studied and most probable alleles to be modifiers of clinical response to IFNβ are HLA-DRB1, DQA1, DQB1 and also HLA-DR2 haplotype; but there are not enough strong studies to support this important role for these genes till now [4,12–15]. Since we have some recent findings to support a role for HLA-DRB1 as the most important gene in susceptibility to MS in Caucasian and Iranian patients [11,16,17].