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Thread: Major histocompatibility complex genes (HLA) confirmed to be associated with multiple sclerosis

  1. #1

    Major histocompatibility complex genes (HLA) confirmed to be associated with multiple sclerosis

    For decades, scientists have been searching for a potential genetic basis for multiple sclerosis. This is the first definitive study that show a significant association of one class of genes to MS. This is important not only from the viewpoint of diagnosing MS but yields clues to the treatment of the the condition. About a decade ago or more, scientists realized the MS is essentially an auto-immune disease but the cause of the autoimmunity was not well understood. This study suggests that the disease is associated with specific major histocompatibiity genes.

    Wise.

    http://www.sciencedaily.com/releases...0922020320.htm
    Date: 2005-09-23
    Definitive Gene Screen Confirms Multiple Sclerosis Suspects

    San Diego -- A cluster of genes on chromosome six is the only one that plays a significant role in multiple sclerosis (MS), according to the most complete genetic study to date in the disorder, presented at the 130th annual meeting of the American Neurological Association in San Diego.

    "Our results confirm the strong role of the major histocompatibility complex genes in MS, and provides a definitive statement that no other region of the genome harbors a gene with a similar overall influence on MS genetics," said Jonathan Haines, Ph.D, of Vanderbilt University in Nashville, Tennessee, who presented on behalf of the International Multiple Sclerosis Genetics Consortium.

    "A detailed examination of the major histocompatibility complex is critically important," said Haines, who suggests that this study may have profound implications for the future directions of MS genetics research.

    The major histocompatibility complex (MHC) is a cluster of genes that play a critical role in the recognition of cells in the body as belonging to the body, i.e., not intruders such as bacteria or other pathogens.

    When this system of recognition breaks down, the immune system may mistakenly launch an attack against cells, as happens in MS. Researchers believe that some genetic variations in MHC genes make people more susceptible to whatever environmental causes also contribute to MS.

    Haines is one of the founders of an international team of researchers from many institutions that collected genetic data on 730 families with more than one case of MS from Australia, Scandinavia, the United Kingdom, and the United States.

    Previous studies have implicated the MHC, but also regions on other chromosomes, as harboring genes that increase MS risk. Haines suggests that these studies failed to include enough subjects.

    "This is the largest genetic linkage study on MS, and the first to be done using the latest technology, which provides very detailed coverage of the entire human genome," said Haines. "Other genes may still play an important role in MS, but finding them will require using new genomic techniques."

    Multiple sclerosis is an enigmatic disease of the nervous system and results in the loss of myelin, a substance that normally insulates nerve fibers and speeds electrical conduction through the fibers. Patches of inflammation (known as 'plaques') occur throughout the brain and spinal cord resulting in the loss of myelin and sometimes the nerve fibers themselves.

    Depending on which nerve fibers are hindered, patients can experience problems ranging from weakness and clumsiness to numbness, visual disturbances, and even emotional and intellectual alterations. In some patients, MS manifests itself in cycles of relapse and remission and patients may show little sign of the disease between attacks.

    ###
    [Background/Abstract]

    A high density screen for linkage in multiple sclerosis
    Jonathan L. Haines, Ph.D. (presenting on behalf of the International Multiple Sclerosis Genetics Consortium - IMSGC).
    Nashville, TN

    This abstract describes the results of what we would consider to be the definitive multiple sclerosis linkage screen. The power of the study is so great that it is virtually certain that all susceptibility loci with effects large enough to be detectable by linkage have been found. The value of a definitive reliable linkage map cannot be overemphasized. The results from this study have profound implications for the future study of the genetics of this complex disorder and enable accurate minimum requirements to be determined for future studies. This is clearly a critical development in the field.

    Ten centimorgan microsatellite map have been the standard tool used for whole genome linkage screening since the mid 1990's and to date 11 screens employing this methodology have been published in multiple sclerosis. However the scale and quality of the data in these studies is limited. In order to establish a definitive linkage map we have typed 4506 single nucleotide polymorphism markers in a set of 730 multiplex families from Australia, Scandinavia, the United Kingdom and the United States, which together provide 945 affected relative pairs. Highly significant linkage is observed in the region of the Major Histocompatibility Complex (lod score 11.7) and suggestive linkage is identified on chromosome 17 and 5. Ordered Sub-set analysis identifies a further locus on chromosome 19. The mean information extraction provided by the marker panel is 79.3% (range 42.4 - 91.3%) and the observed Mendelian inconsistencies suggests that within this data set the genotyping error rate is just 0.002%. These data have profound implications for the future directions of multiple sclerosis genetics research and suggest that previous efforts in this area are almost all substantially underpowered. In the future association studies will need to include at least 500-1000 cases.

  2. #2
    Here are recent abstracts for the genetic analyses showing HLA antigen association with multiiplee sclerosis. The first paper is of particular interest because it was carried out in African Americans and suggests that the gene for MS susceptibility in African Americans may be on chromosome 1 rather than chromosome 6 (where the HLA antigens are located). The second paper analyzed mostly Canadian and Finnish families, finding a close association of HLA-DRB1 gene to multiple sclerosis. Wise.


    1. Reich D, Patterson N, Jager PL, McDonald GJ, Waliszewska A, Tandon A, Lincoln RR, Deloa C, Fruhan SA, Cabre P, Bera O, Semana G, Kelly MA, Francis DA, Ardlie K, Khan O, Cree BA, Hauser SL, Oksenberg JR and Hafler DA (2005). A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis. [1] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16186815
    2. Lincoln MR, Montpetit A, Cader MZ, Saarela J, Dyment DA, Tiislar M, Ferretti V, Tienari PJ, Sadovnick AD, Peltonen L, Ebers GC and Hudson TJ (2005). A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants. [1] Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [3] These authors contributed equally to this work. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16186814
    Last edited by Wise Young; 09-29-2005 at 02:07 AM.

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