Multipe Sclerosis - Pathology
Genetic predisposition -
updated: 27 October 2009
Multiple sclerosis genetics: leaving no stone unturned
Genes Immun. 2005 Aug;6(5):375-87
Oksenberg JR, Barcellos LF.
Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how someone responds to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and significant environmental influences. Equally significant, it is also likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic, and phenotypic information in well-controlled study groups will define a useful conceptual model of pathogenesis and a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies.
Publication Types:
Online - Abstract
New insights into the genetics of multiple sclerosis
J Rehabil Res Dev. 2002 Mar-Apr;39(2):201-9
Baranzini SE, Oksenberg JR, Hauser SL.
Tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develop in genetically susceptible individuals after exposure to a causal agent that is yet undefined. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, posttranscriptional regulatory mechanisms, and significant environmental influences. Equally significant is that genetic heterogeneity also likely exists, meaning that specific genes influence susceptibility and pathogenesis in some affecteds but not in others. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen significant progress in the developments of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and to define the pathological basis of demyelination. These developments have set the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. The identification and characterization of the genes are likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.
Publication Types:
Online - Abstract
Genetic analysis of multiple sclerosis
Curr Neurol Neurosci Rep. 2002 May;2(3):259-66.
Compston A, Sawcer S.
The increased recurrence risk within families indicates a role for genetic factors in the etiology of multiple sclerosis. Genes may influence susceptibility to the development of multiple sclerosis and the subsequent course of the disease. To date, associations have only been demonstrated consistently with class II major histocompatibility complex (MHC) alleles. The relatively low yield from additional candidate gene studies is only modestly advanced by several whole-genome linkage analyses, and by the first in a series of planned whole-genome linkage disequilibrium screens for allelic associations. The aims of linkage and association are to narrow the search for chromosomal regions encoding genes for multiple sclerosis and, with information from the human gene project, suggest new positional candidates. In time, it is expected that these genes will include some that confer susceptibility to the general process of autoimmunity, others that are specific for multiple sclerosis in all populations, some that act only in defined ethic groups, and those that determine particular phenotypes or shape the clinical course. These genetic analyses are predicated on the assumption that multiple sclerosis is one disease; a major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis. When eventually in place, the potential of this genetic knowledge for improved understanding of the pathogenesis of multiple sclerosis and designing novel treatments is considerable.
Publication Types:
Online - Abstract
The genetics of multiple sclerosis
J Neurovirol. 2000 May;6 Suppl 2:S5-9
Compston A.
Epidemiological studies implicate an interplay between genetic and environmental factors in the aetiology of multiple sclerosis. The classical genetic observations suggest that multiple sclerosis is a complex trait in which susceptibility is determined by several genes acting independently or epistatically. The main dividend from understanding the genetic basis of susceptibility in multiple sclerosis will be an improved understanding of the pathogenesis. To date, candidate gene approaches have proved relatively unrewarding other than in establishing the association with alleles of the major histocompatibility complex (MHC). In common with most other complex traits, no major susceptibility gene has been identified through full genome screens but regions of interest have provisionally been identified. An important part of future studies in the genetics of multiple sclerosis will be to resolve the question of disease heterogeneity.
Publication Types:
Online - Abstract
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