Genetic variation and autoimmune disease

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Genetic variation and autoimmune disease

Postby dignan » Thu Jan 26, 2006 8:35 am

Another worthwhile effort...



Researchers Identify Gene Sequences Associated With Favourable Immune Functions

Sequence differences in less than 0.2% of the 3-billion-base human genome play a vital role in a bewildering variety of human disease. Today, researchers from the Wellcome Trust Sanger Institute and the Cambridge University’s Cambridge Institute for Medical Research, together with international colleagues report in PLoS Genetics their detailed maps of differences implicated in disease as well as genes that are unchanged in recent human history.

The Major Histocompatibility Complex (MHC) consists of hundreds of genes on human chromosome 6 that are important in most autoimmune conditions, when our biological defences turn on our own systems. The MHC has the major role in type 1 diabetes and rheumatoid arthritis. The MHC is also pivotal in response to infection, including malaria and AIDS.

Genes in the MHC can differ dramatically between people, and the differences among us affect medical events as diverse as tissue transplant rejection, arthritis, asthma and disease resistance. A detailed study of this region in different people will shed light on which genes are most important.

“We analysed the entire MHC region in detail from three individuals that carried different susceptibility to disease,” explained Dr Stephan Beck, leader of the team at the Wellcome Trust Sanger Institute. Key differences were then further analysed in a much larger population of 140 DNA samples.

“Within the sea of over 20,000 sequence variations across the 4 million MHC bases, we found one island of stability,” continued Dr Beck. “A region of 160,000 bases that is up to 200-fold less variant between chromosomes sharing part of the same HLA type, suggesting these individuals most likely shared a common ancestor as recently as 50,000 years ago.”

Swapping of ancestral sequence blocks is a potential mechanism (identity-by-descent) whereby certain gene combinations, which presumably have favoured immunological advantage (e.g. resistance to infectious disease), can spread across haplotypes and populations.

Professor John Trowsdale, at the Department of Pathology, University of Cambridge, said, “The region, called DR-DQ, where we find this island of stability is one of the most variable in our genome, yet in some people it has been ‘fixed’. We suggest that ancestral DR-DQ blocks have been shuffled into different MHC backgrounds and subsequently expanded in frequency across European populations.

“These ‘fixed’ haplotypes might then have expanded because they protected against infection and disease. We hope to show, in further studies, whether this stable region was a key to disease resistance in our recent past.”

The study further described over 300 amino acid changing variants in gene sequences. These variants are strong candidates for functional studies to understand the role of variation in MHC-associated disease.

Autoimmune disease affects about 3 million people in the UK. The three haplotypes studied here display different susceptibilities to diseases such as type 1 diabetes, myasthenia gravis and multiple sclerosis.

For some common autoimmune diseases the MHC provides by far the largest genetic contribution by a single chromosome region. For example, the MHC accounts for at least 30% of the familial aggregation in type 1 diabetes and rheumatoid arthritis.

“Data generated by projects such as the MHC Haplotype Project will feed into the recently announced Wellcome Trust Case-Control Consortium,” explained Professor John Todd, Professor of Medical Genetics at the Cambridge Institute for Medical Research, “and the WTCCC search for the genetic signposts for eight common diseases will be accelerated by the new markers reported here. At an ever increasing rate, we are developing the necessary tools and sample collections to make a real difference to the study, diagnosis and, we hope, treatment of diseases such as TB, coronary heart disease, diabetes and rheumatoid arthritis.”

The MHC Haplotype Project is creating a public resource to assist the discovery of genetic factors influencing these medical traits and to shed light on the evolution of the MHC. Access to complete sequences across several MHC haplotypes that exhibit differences in disease susceptibility will help researchers to home in on specific variants (susceptibility alleles) and to rule out regions contributing to a given disease.

Haplotypes are combinations of gene and sequence variants that tend to occur together in an individual genome. This may be purely fortuitous, or it may reflect selection of given combinations (they have been successful in the past), or it may reflect a population bottleneck, where only a few, perhaps similar, genomes have contributed to the further population growth.

The MHC is among the most gene-dense regions of the human genome and the most variable, as might be expected from a region involved in fighting infection (as well as other functions). Over evolutionary time, the MHC has been driven to become the most variable region of our genome.

The MHC Haplotype Project is studying in fine detail the sequence of eight of the most common human haplotypes, selected for conferring protection against or susceptibility to common disease. The detailed analysis of the third of these eight is reported here and compared with the two previously described.

The COX haplotype has been associated with susceptibility to a wide range of diseases, including type 1 diabetes, systemic lupus erythematosus and myasthenia gravis.

The PGF haplotype provides protection against type 1 diabetes and predisposes to other diseases such as multiple sclerosis and systemic lupus erythematosus.

The QBL haplotype is positively associated with Graves’ disease and type 1 diabetes.

http://www.innovations-report.com/html/ ... 54356.html
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Postby OddDuck » Thu Jan 26, 2006 11:06 am

dignan,

Please don't kill me here, and I hate to say it, but all of this research regarding MHC has been going on for many years. My first neuro, when he was at the Mayo, did research on MHCI and II back in the 90s.

And David Hafler has been studying MHC for years, also.

The reason why I'm bringing this to everyone's attention is that I'm beginning to see that the only thing that is happening here lately in the news with regard to MS is that the same theories and studies are only being re-circulated, that was originally discovered many years ago!

I would like to know, since they already know this, why they keep trying to claim it's a "new" discovery!? And since they have known about all this for many years, where are the new drugs that work on all these findings?

I wrote about MHC in my original narrative back in 2004, also.

Additional discussion can be found at:

http://www.thisisms.com/modules.php?nam ... hlight=mhc

And here is an example of a 1998 study with regard to MHC. They know MHC is involved. Always have known. :(

Nat Med. 1998 Feb;4(2):187-93. Related Articles, Links

Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis.

Rivera-Quinones C, McGavern D, Schmelzer JD, Hunter SF, Low PA, Rodriguez M.

Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Demyelination alone has been considered sufficient for development of neurological deficits following central nervous system (CNS) disease. However, extensive demyelination is not always associated with clinical deficits in patients with multiple sclerosis (MS), the most common primary demyelinating disease in humans. We used the Theiler's murine encephalomyelitis virus model of demyelination to investigate the role of major histocompatibility complex (MHC) class I and class II gene products in the development of functional and neurophysiological deficits following demyelination. We measured spontaneous clinical activity by two independent assays and recorded hind-limb motor-evoked potentials in infected class I-deficient and class II-deficient mice of an identical genetic background as well as in highly susceptible SJL/J mice. The results show that despite a similar distribution and extent of demyelinated lesions in all mice, only class I-deficient mice were functionally normal. We propose that the mechanism by which demyelinated class I-deficient mice maintain neurologic function results from increased sodium channel densities and the relative preservation of axons. These findings are the first to implicate a role for MHC class I in the development of neurological deficits following demyelination.

PMID: 9461192 [PubMed - indexed for MEDLINE]


Ok, Ill shut-up. Don't anybody kill me here!

Take care!!!

Deb
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Postby dignan » Thu Jan 26, 2006 7:00 pm

I think this is the heart of the matter...


"The MHC Haplotype Project is studying in fine detail the sequence of eight of the most common human haplotypes, selected for conferring protection against or susceptibility to common disease. The detailed analysis of the third of these eight is reported here and compared with the two previously described.

The COX haplotype has been associated with susceptibility to a wide range of diseases, including type 1 diabetes, systemic lupus erythematosus and myasthenia gravis.

The PGF haplotype provides protection against type 1 diabetes and predisposes to other diseases such as multiple sclerosis and systemic lupus erythematosus.

The QBL haplotype is positively associated with Graves’ disease and type 1 diabetes."



While the involvement of this area in MS might have been known or suspected for a long time, it looks like they are only doing a thorough analysis of the complete data on the MHC now.
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