Genetics of multiple sclerosis
Section snippets
Multiple sclerosis is a complex genetic disease
The cause of multiple sclerosis (MS) is unknown, but it is widely believed to be an autoimmune disease occurring in genetically susceptible individuals after exposure to as-yet undefined environmental factors. The genetic etiology is indicated foremost by the recurrence risk in family members of the affected individual [1], [2]. One measure of familial aggregation is the λs statistic, defined as the ratio of the lifetime risk to siblings of affected individuals (Ks) to the population prevalence
Narrowing the search and identifying the multiple sclerosis genes
On February 15, 2001, the International Human Genome Sequencing Consortium and the company Celera simultaneously reported the completion of the first draft of the human genome sequence. This historic scientific milestone provided a direct way to connect a chromosomal region with its DNA sequence and gene content and dramatically changed the ability to examine genetic variation as it relates to human disease. An early gain of the Human Genome Project was the development of detailed maps of
Linkage studies in multiple sclerosis
The three pivotal whole genome screens performed in multiple affected families that have MS were completed and published by American, Canadian, and United Kingdom researchers almost a decade ago [11], [12], [13]. Since then, follow-up screenings in confirmatory and additional data sets also have been completed. The studies confirmed the known association with the HLA class II DR2 haplotype (HLA-DRB1∗1501-DQA1∗0102-DQB1∗0602) but failed to find other major loci in MS. Altogether, the screens
MS1, chromosome 6p21.3, the major histocompatibility complex
The human MHC (the human leukocyte antigen [HLA] system) consists of linked gene clusters located at 6p21.3, spanning almost 4 million base pairs (Fig. 2). HLA molecules are cell-surface glycoproteins whose primary role in an immune response is to display and present short antigenic peptide fragments to peptide/MHC-specific T cells. Many of the HLA class I and II genes are highly polymorphic, resulting in the generation of enormously diverse numbers of different genotypic combinations or
MS2, chromosome 19q13
Genomic screens have shown support for linkage to this region and a meta-analysis [16] of all four pivotal genomic screens identified 19q13 as a significant disease locus. Additional evidence for this region came from allelic association and from follow-up studies [63], [64], [65], [66]. Overall, the effect of the 19q13 locus likely is moderate, with an estimated locus-specific λs = 1.5, thus accounting for 4% to 6% of the overall genetic component in MS. On chromosome 19q13, the minimal critical
MS3, chromosome 17q21-23
The chromosomal segment 17q21 was highlighted first in the genome scan performed in MS pedigrees collected in the United Kingdom [13] and confirmed in Finish families [73]. On chromosome 17q21, the minimal critical region spans between 36 and 46 cM and includes 331 genes. Further support for chromosome 17q21 was detected in follow-up studies in both populations [74], [75], [76] in association screening in several European and migrant European populations (//www.mrc-bsu.cam.ac.uk/Msgenetics/GAMES
Future directions
Although genetic components in MS clearly are present, the lack of an obvious and homogeneous mode of transmission has prevented the efficient application of classical genetic epidemiologic techniques. When a disease results from highly penetrant genomic variants, genetic linkage is a powerful method for significantly reducing the chromosomal regions that need to be examined for gene discovery. The power of linkage analysis to detect multiple signals of modest strength is limited, however. It
Summary
Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing MS, how the disease progress, 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. Some loci may be involved in the initial pathogenic events, whereas others could influence the development and progression of the disease. Their incomplete penetrance and moderate individual
References (81)
- et al.
Evidence for genetic basis of multiple sclerosis
Lancet
(1996) - et al.
Multiple sclerosis: genomic rewards
J Neuroimmunol
(2001) - et al.
Histocompatibility determinants in multiple sclerosis
Lancet
(1973) - et al.
Association of susceptibility to multiple sclerosis in Sweden with HLA class II DRB1 and DQB1 alleles
Hum Immunol
(1994) - et al.
HLA-DQA1 and HLA-DQB1 genes may jointly determine susceptibility to develop multiple sclerosis
Hum Immunol
(1991) - et al.
Evidence of linkage with HLA-DR in DRB1∗15-negative families with multiple sclerosis
Am J Hum Genet
(2001) - et al.
Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis
Am J Hum Genet
(2002) - et al.
The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci
Hum Immunol
(2001) - et al.
Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis
Am J Hum Genet
(2002) - et al.
Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans
Am J Hum Genet
(2004)
The DRB1 Val86/Val86 genotype associates with multiple sclerosis in Australian patients
Hum Immunol
Human leukocyte antigen class II immune response genes, female gender, and cigarette smoking as risk and modulating factors in abdominal aortic aneurysms
J Vasc Surg
HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course
Am J Hum Genet
HLA profiles in multiple sclerosis suggest two forms of disease and the existence of protective haplotypes
J Neurol Sci
Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis
J Neurol Sci
A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis
J Neurol Sci
Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis
Am J Hum Genet
Association of apolipoprotein E polymorphism to clinical heterogeneity of multiplesclerosis
Neurosci Lett
Genomewide scan of multiple sclerosis in Finnish multiplex families
Am J Hum Genet
Age-adjusted recurrence risks for relatives of patients with multiple sclerosis
Brain
Factors influencing sib risks for multiple sclerosis
Clin Genet
Corrections to linkage strategies for genetically complex traits. III. The effect of marker polymorphism on anlaysis of affected relative pairs
Am J Hum Genet
A genetic basis for familial aggregation in multiple sclerosis
Nature
The British Isles survey of multiple sclerosis in twins
Neurology
Twin concordance and sibling recurrence rates in multiple sclerosis
Proc Natl Acad Sci USA
Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus
Nat Genet
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Nature
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Nature
A full genome search in multiple sclerosis
Nat Genet
A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex
Nat Genet
A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22
Nat Genet
A meta-analysis of genomic screens in multiple sclerosis
Mult Scler
Meta-analysis of genome searches
Ann Hum Genet
A meta-analysis of whole genome linkage screens in multiple sclerosis
J Neuroimmunol
Variation in genes regulating the immune system and relationship to disease
HLA antigens and multiple sclerosis
Tissue Antigens
Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia
Hum Mol Genet
Genetic factors and the founder effect explain familial MS in Sardinia
Neurology
Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders
Ann Neurol
Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK
J Neurol Neurosurg Psychiatry
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NOS2A as a candidate gene in Relapsing-Remitting Multiple Sclerosis: A haplotype study using selected subsets of single nucleotide polymorphisms
2011, Journal of the Neurological SciencesCitation Excerpt :Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of multifactorial etiology, in which both genetic and environmental factors play a role in susceptibility [1,2].
Tumefactive multiple sclerosis: An uncommon diagnostic challenge
2011, Journal of Chiropractic MedicineCitation Excerpt :Although the cause of MS is unknown, it is considered an autoimmune disease occurring in genetically susceptible individuals. Factors that impact the genetic susceptibility for MS are infectious, nutritional, climatic, or environmental.7 Triggers for onset or relapse may include pregnancy, stress, trauma, anesthesia, surgery, or vaccinations.4
Multiple sclerosis: Could it be an epigenetic disease?
2008, Medical HypothesesPreliminary evidences of a NOS2A protective effect from Relapsing-Remitting Multiple Sclerosis
2008, Journal of the Neurological SciencesSerum IgE reactive against small myelin protein-derived peptides is increased in multiple sclerosis patients
2006, Journal of Neuroimmunology
The authors are supported by the National Multiple Sclerosis Society, the National Institutes of Health, and the Nancy Davis and Montel Williams Foundations.