Multiple Sclerosis Gene Research Articles

Comparative Expression of Human Endogenous Retrovirus-W Genes in Multiple Sclerosis

Human endogenous retroviruses (HERVs) have been associated with multiple sclerosis (MS) pathogenesis. Several related HERV-W sequences have been implicated in disease occurrence and progression; the MS retrovirus (MSRV) is one such element whose envelope protein has been recently demonstrated to be involved in innate immune pathogenesis. To distinguish MSRV from other HERV-W sequences we analyzed the relative abundance of individual HERV-W env sequences by employing a real-time PCR approach using specific oligonucleotide primers and tissue samples from MS and non-MS patients. Our analyses reveal that ERVWE1 env-encoding DNA and RNA exhibited increased detection (p < 0.05) and expression (p < 0.01) in the brains of MS patients. Similarly, ERVWE1 env transcripts were inducible in glial cells (p < 0.05), while comparable changes in MSRV abundance were not observed. These results indicate that individual HERVs might have distinct roles in MS pathogenesis.

The role of hereditary spastic paraplegia related genes in multiple sclerosis

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss. The clinical similarities between Hereditary Spastic Paraplegia (HSP) and progressive MS, along with their analogous profiles of axonal loss in the long tracts, make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS. A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity. The MS cases were taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date. Genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP (Paraplegin, NIPA1, KIF5A, HSPD1, Atlastin, Spartin, Spastin, PLP1, L1CAM, Maspardin and BSCL2) play a role in susceptibility to, or modifying the course of, MS, although small effects of these genes cannot be ruled out.

Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations

We have investigated the genetic involvement of the CD4 and the LAG3 genes, two appealing candidates for MS due to their suggested role in MS pathology. We genotyped a Swedish case–control material consisting of 920 MS patients and 778 controls in an initial study of CD4, three SNPs showed a significant association with MS. An independent material consisting of 1720 Nordic MS patients and 1416 controls were used for confirmation of associated markers in CD4 and to do a confirmative study of the LAG3 gene from previous findings. The result, including a total of 2640 MS patients and 2194 controls shows no significant association with CD4 and LAG3 and MS. We conclude that these genes are of minor importance in regard of genetic predisposition to the MS.

Lack of association with the CD28/ CTLA4/ ICOS gene region among Norwegian multiple sclerosis patients

Chromosome region 2q33 encodes several regulators of the immune system, among these the CD28, CTLA4, and ICOS molecules. Involvement of these genes in multiple sclerosis (MS) is not yet clear. We investigated six microsatellites and three SNPs in a relatively large and clinically well characterised Norwegian MS cohort. No associations were observed for any of the markers analysed in 575 MS patients and 551 controls. Associations were neither found when stratifying the material for the HLA-DRB1*1501, DQB1*0602 haplotype, gender, age at onset, disease course nor familial aggregation. In conclusion, this study could not confirm association with the CD28/ CTLA4/ ICOS gene region.

IFNAR1 and IFNAR2 polymorphisms confer susceptibility to multiple sclerosis but not to interferon-beta treatment response

We investigated the role of three polymorphisms in the IFNAR1 (SNPs 18417 and -408) and IFNAR2 (SNP 11876) genes in multiple sclerosis (MS) susceptibility and in the IFNβ treatment response in a group of 147 patients and 210 controls undergoing interferon therapy during the last 2 years. Only the 18417 and the 11876 SNPs showed an association with disease susceptibility ( p = 0.001 and 0.035, respectively) although no differential genotype distribution were observed between interferon responders and non-responder MS patients. No alteration of the expression level of IFNAR-1 was observed with respect to the −408 genotypes or to interferon treatment response. These data suggest a role for the IFNAR pathway in susceptibility to MS.

Identifying disease modifying genes in multiple sclerosis

Evidence is mounting that genetic variation influences not only susceptibility to multiple sclerosis (MS), but also its course and severity. Identification of disease modifying genes, however, poses unique challenges, especially on how to classify the course and outcome of the disease in ways that may be relevant to analysis of biological factors that might be influenced by genes. The power of the statistical approaches to detect small effects of individual genes in complex disorders such as MS is problematic, and approaches to estimate power must be appropriate for the data. Nonetheless, using contemporary schemes of classification, genetic variants that influence disease course have been found; in fact, a small number have been confirmed to influence disease course in two or more independent studies. This review addresses strategies relevant to identification of disease modifying genes in MS, and summarizes and critically evaluates the current state of knowledge in this area.

Peripheral blood cell bulk cultures are not suitable for the analysis of the genetic control of T-cell cytokine function

Recently evidence has been provided for a genetic control of T-cell dependent cytokine production by HLA-class II. Candidate genes in multiple sclerosis, a T-cell mediated autoimmune disease, are the disease-associated DR2, DQ6, Dw2 haplotype. Previous observations by us and others imply a HLA-DR2 dependent propensity of antigen-specific T-cell lines to produce increased amounts of TNF-α/β. Here, we tested a possible association between HLA or disease status with cytokine production employing the simple and widely used method of bulk cultures. Peripheral blood cells of 48 patients and 68 healthy individuals were analyzed. We observed no significant differences of the cytokine production in relation to disease status or any HLA polymorphism. Our data indicate that, in contrast to monoclonal T-cell cultures, bulk cultures are not suitable to detect immunogenetic control of T-cell function.

T Cell Receptor V Genes in Multiple Sclerosis: Increased Use of TCRAV8 and TCRBV5 in MBP-Specific Clones

It is probable that myelin-reactive T cells, including those specific for myelin basic protein (MBP) contribute to the pathogenesis of multiple sclerosis (MS). Although many studies have characterized the specificity, MHC restriction, and V gene use of MBP-specific T cells, there is little agreement as to whether there are differences between MS and controls, and how HLA-DR2, a risk factor for MS, might influence selection of MBP-specific T cells. We here discuss models in which MHC class II alleles could help shape the TCR repertoire, and then review more than 750 clones reported in the literature. The major finding from our analysis is that both TCRAV8 and BV5, but not BV6 were utilized more frequently in MS patients than non-MS patients in response to MBP, although no differences were found between DR2+ versus DR2−donors. These data indicate HLA-independent differences in the T cell repertoire between MS patients and controls that may be important for targeted TCR-based therapy. Moreover, we conclude that (1) HLA-DR alleles preferentially restrict MBP responses, although MS patients tend to use HLA-DQ and-DP alleles more often than control donors; (2) HLA-DR2 alleles are used to restrict only about half the MBP responses in MS patients, significantly less than in control patients; (3) the DRB*11501 and DRB5*0101 subtypes within the Dw2 haplotype are used relatively equally to restrict MBP responses. In this context, we review the results of our previous clinical trials in progressive MS patients, demonstrating the ability of TCRBV5S2 peptides to induce clinically relevant regulatory responses that inhibit MBP-specific Th 1 cells through a bystander suppression mechanism.

Polymorphisms of cytokines and adhesion molecules genes in multiple sclerosis

Polymorphisms of cytokines and adhesion molecules genes in multiple sclerosis

Role of myelin basic protein and proteolipid protein genes in multiple sclerosis: single strand conformation polymorphism analysis of the human sequences

Role of myelin basic protein and proteolipid protein genes in multiple sclerosis: single strand conformation polymorphism analysis of the human sequences

Role of myelin basic protein and proteolipid protein genes in multiple sclerosis: single strand conformation polymorphism analysis of the human sequences.

Susceptibility to multiple sclerosis (MS) is widely held to have a strong genetic component. While the identities of genes conferring susceptibility are currently unknown, possible candidates include those genes coding for proteins which function in central nervous system (CNS) myelin. Two such genes are the human myelin basic protein (MBP) and proteolipid protein (PLP) genes, whose products make up approximately 80% of the total protein in CNS myelin. The association of a variable number tandem repeat (VNTR) 5' to the human MBP gene with MS has been the subject of conflicting reports. Here we test the hypothesis that mutations in the human MBP and PLP genes might be associated with MS by examining the entire expressed sequence of both genes by single strand conformation polymorphism (SSCP) analysis, using a panel of 71 MS patients and 71 controls. We have also re-examined the VNTR region in patients and controls. Three base changes were found in the human PLP gene and nine base changes in the human MBP gene; these were essentially equally distributed between patients and controls. No preferential distribution of various alleles of the VNTR between patients and controls was found. Although intronic and regulatory regions have not been examined, it would appear unlikely that mutations in these genes coding for the two major CNS myelin proteins contribute significantly to genetic susceptibility to MS.

Immune system genes in multiple sclerosis: genetic association and linkage analyses on TCR β, IGH, IFN- γ and IL-1ra/IL-1 β loci

The role of genetic factors in the etiology of multiple sclerosis (MS) has been clearly demonstrated but the loci determining susceptibility to this disease remain largely unidentified. A contribution from several immune system genes has been suggested based on animal models and association/linkage analyses on MS patients and families. With the exception of the findings from the HLA complex, studies on candidate immune system genes have provided controversial results. Here we have performed genetic association and linkage analyses on four chromosomal regions containing immune system genes. A possible role for each of these loci in MS has been previously suggested. In data-sets derived from the Finnish population we found no evidence for contribution of the T-cell receptor β chain (TCR β chromosome 7q35), immunoglobulin heavy chain (IGH chromosome 14q32), interferon- γ (IFN- γ chromosome 12q14-q15) or interleukin-1 receptor antagonist/interleukin-1 β (IL-1ra/IL-1 β chromosome 2q14-q21) loci in the genetic susceptibility to MS.

1-31-24 Immune system genes in multiple sclerosis: Genetic association and linkage analyses on TCRβ, IGH, IL-1ra/IL-1β and IFN-γ loci

1-31-24 Immune system genes in multiple sclerosis: Genetic association and linkage analyses on TCRβ, IGH, IL-1ra/IL-1β and IFN-γ loci

No linkage or association of a VNTR marker in the junction region of the immunoglobulin heavy chain genes in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system. Autoantibodies are though to participate in the pathogenesis. Previous reports on the role of immunoglobulin (Ig) variable gene segments in MS are contradictory. Here, by using a highly polymorphic variable number tandem repeat (VNTR) marker located in the centre of the IgH chain locus, we demonstrate a lack of linkage and association with MS in 34 multiplex families and 113 sporadic MS patients in Sweden. Stratification for the presence or absence of the MS-associated HLA-Dw2 haplotype did not influence the negative outcome. We conclude that the IgH chain genes are unlikely to play a role in genetic susceptibility to MS in the Swedish population.

Mono-oligoclonal expansion of γ/δ T cells as evidenced by limited Vδ-Jδ rearrangement of TCRδ chain genes in multiple sclerosis

Mono-oligoclonal expansion of γ/δ T cells as evidenced by limited Vδ-Jδ rearrangement of TCRδ chain genes in multiple sclerosis

Mono-oligoclonal expansion of γ/δ T cells as evidenced by limited Vδ-Jδ rearrangement of TCRδ chain genes in multiple sclerosis

Mono-oligoclonal expansion of γ/δ T cells as evidenced by limited Vδ-Jδ rearrangement of TCRδ chain genes in multiple sclerosis

Linkage analysis of HLA class II genes in Swedish multiplex families with multiple sclerosis.

We assessed the influence of human leukocyte antigen (HLA) class II as susceptibility genes in multiple sclerosis (MS) by linkage analysis. Other research groups, who have shown negative results in studies on affected sibling pairs, have questioned the influence of the HLA class II genes, although they confirmed the association of the DR15,DQ6,Dw2 haplotype to MS. In this report, we find a significant lod score (>3) when using a 2-point linkage analysis of 49 small Swedish nuclear MS families with at least two affected family members, typed for HLA class II alleles by PCR amplification with sequence-specific primers. We obtained maximum lod scores when we used dominant or intermediate models with low penetrance. We found that the positive effect on the total lod score was not confined to those families carrying the presumed susceptibility HLA-haplotype Dw2. This observation supports the notion of a functional role of the HLA class II molecules themselves in MS. In addition, we observed significant transmission distortion and an intrafamilial association of the MS-associated class II haplotype HLA-Dw2. These results indicate that the HLA class II genes are of clear importance for MS in the studied population.

Genetic epidemiology of multiple sclerosis.

Multiple sclerosis appears to be a complex trait determined by genes and environmental factors. This hypothesis is increasingly supported by genetic epidemiological studies of large populations. Well ascertained studies of adoptees and half siblings indicate that familial aggregation is genetic. These results have important implications for the nature of environmental factors influencing susceptibility to multiple sclerosis. These appear to act at a population level and probably exert an influence on risk that matches or exceeds that from any single genetic locus. The identification of susceptibility genes in multiple sclerosis will be difficult.

Genetic segregation of multiple sclerosis and histocompatibility (HLA) haplotypes.

The possibility that a gene determining susceptibility to multiple sclerosis (MSS) may be closely linked to the major histocompatibility locus (HLA) is suggested by observation of a loose association between multiple sclerosis (MS) and certain HLA determinants. In the present study, the possible association was analyzed by studying the segregation of MS and the HLA haplotypes in families with more than one case of MS. Analysis of 48 published families revealed that the haplotype shared by those with MS within the family was also shared by those without clinical signs of MS at close to the 50% frequency expected by chance. Thus, we were unable to demonstrate that MS is associated with one HLA defined parental haplotype. We discussed reasons for this apparent failure to demonstrate existence of an MSS gene using available multiplex MS families.