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Gene mutation linked to Chrohns disease may require specific viral infection to kick

Discussion in 'Other Health News and Research' started by Rita, Jun 24, 2010.

  1. Rita

    Rita Senior Member

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    Gene mutation linked to Chrohns disease may require specific viral infection to kick in
    June 24, 2010

    Scientists have shown that a specific virus can interact with a mutation in the host's genes to trigger disease. The observation may help explain why many people with disease-risk genes do not actually develop disease.

    Researchers at Washington University School of Medicine in St. Louis found that three factors were necessary in mice to create a condition similar to the human bowel disorder Crohn's disease [colitis]:

    A mutated gene,

    Exposure to a damaging chemical,

    And infection with a specific virus.

    The report was published online June 25 in Cell (Virus plus susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.)

    Complex diseases like Crohn's are influenced by both genetic and environmental factors; other examples include cancer, heart disease, diabetes, Alzheimer's disease, multiple sclerosis and Parkinson's disease.

    Studies of these conditions have shown that having a gene linked to disease does not always lead directly to that disease. This has prompted searches for other factors that interact with genes to trigger complex diseases, including exposure to toxins or infection with microorganisms.

    Researchers say the new findings suggest that viruses may provide some of the missing links between genes, environment and disease.

    "We've provided a very specific example of a virus triggering a complex disease - if the mice don't have the virus, they don't get the symptoms," says co-senior author Herbert W. "Skip" Virgin, MD, PhD, head of Pathology & Immunology at WU School of Medicine.

    "Many viruses infect nearly 100% of people, and when their genes interact with our genes, they may be contributing to such diseases."

    Virgin and co-senior author Thaddeus S. Stappenbeck, MD, PhD, associate professor of Pathology & Immunology, also found evidence that viruses' roles in complex diseases may be difficult to detect.

    Crohn's disease, which affects approximately 500,000 Americans, causes diarrhea, abdominal pain and infections, and can lead to complications requiring surgery.

    Some people with Crohn's have mutations in their Atg16L1 gene, but the mutations are much more prevalent than the disease.

    "In Western society, about half of all copies of Atg16L1 contain the mutation linked to Crohn's," Stappenbeck says. "That means both copies of this gene are mutated in about one in every three persons. And yet Crohn's occurs in a small fraction of these individuals."

    In an earlier study, Stappenbeck and Virgin learned that mice with mutated Atg16L1 have abnormalities in Paneth cells, which help regulate the gut microbial communities that aid digestion.

    When the model was recreated in a more stringently controlled environment, the Paneth cell abnormalities did not reoccur until researchers infected the mice with a mouse norovirus.

    Versions of this virus that infect humans are infamous for causing difficult-to-control outbreaks of diarrhea on cruise ships, and cause a significant portion of gastroenteritis cases worldwide.

    When they also fed the mice dextran sodium sulfate (DSS), a chemical used to simulate gut injury, additional Crohns-like pathologies appeared, but only in the presence of the mouse norovirus.

    We dont know the details of why DSS works with the virus to help create the model, and we have no evidence as yet that dietary toxins play a similar role in the creation of human Crohns disease," Stappenbeck says. "Given how similar the models symptoms and responses to treatment are to human disease, though, those are issues we will be investigating."

    Stappenbeck notes that the study also doesn't prove that human noroviruses cause Crohn's disease.

    "It suggests that they might be a place to look," he says. "But it's worth emphasizing that we needed the additional damage from DSS, together with the virus and the mutant gene, to trigger the symptoms."

    Scientists have found several genes that influence risk of Crohn's disease. Stappenbeck suggests that there are likely to be several paths to developing the disease that include multiple environmental risk factors.

    When scientists gave the mice a broad-spectrum antibiotic, their symptoms stopped.

    Researchers speculate that the virus and the gene's effects on Paneth cells may be changing the gut microbial community in harmful ways, triggering Crohn's-like pathology.

    It's possible that the antibiotic, which does not affect viruses, clears out the maladjusted community of gut microbes.

    "More immediately, this tells us that how a complex disease responds to antibiotics can't be used to rule out a part for viral contributors in causing that disease," Virgin says.

    "If we hadn't already been aware of the virus's role as a trigger for symptoms, the model's response to the antibiotic would have led us to pin the blame on gut microbes and stop looking at viruses."

    A closely related strain of mouse norovirus with only slight genetic differences could not cause symptoms.

    According to Virgin, the two strains would have been indistinguishable to conventional tests for viral infection, which are based on the types of antibodies found in the blood.

    "Our results show that we can't rely on these tests to determine if a particular strain of virus helps trigger a complex disease," Virgin says.

    Virgin and Stappenbeck plan multiple follow-up investigations, including:

    A more detailed look at how norovirus infection alters the microbial community in the gut of the mice,

    And continued efforts to identify new viruses that infect humans.

    "Viruses are extra genes present in the host," Virgin says.

    "Until we understand how those extra genes interact with our own DNA, we may not be able to assemble a complete picture of how what's in our genes affects what happens to our health."

    _____

    Source: Washington University in St. Louis news release, Jun 24, 2010
  2. Gemini

    Gemini Senior Member

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    Rita,

    Interesting animal model--genes+ infection+ chemical = complex disease

    Thanks for posting the study.

    Gemini
  3. Rosemary

    Rosemary Senior Member

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    Gene + virus + injury = disease?

    Rita Many Thanks for posting this interesting study

    Here is some further information....

    One of the most detailed studies to date of how the interaction between genes and environment results in disease has demonstrated that an inflammatory bowel disease resembling human Crohn's needs a specific mutation, virus, and injury to develop in mice.

    "Environmental genomic issues are tough to crack," said John Mordes, professor of endocrinology at the University of Massachusetts, who has previously characterized a gene-virus interaction in type1 diabetes. "This is a significant contribution to the evolving understanding of how the environment interacts with genomic predisposition."

    The team, led by immunologist Thaddeus Stappenbeck and virologist Herbert Virgin of Washington University School of Medicine, found that the diseased state was brought about by the complex interplay among a mutation in an autophagy-related gene called ATG16L1, a specific virus, a toxic substance, microbes in the rodent's gut, and the rodent's own immune response. The findings appear in a paper that will be published tomorrow in Cell.

    "It's a well-documented scientific example of how very particular environmental events and genes interact to result in disease," said Richard Blumberg, chief of gastroenterology at Brigham and Women's Hospital at Harvard Medical School, who was not involved in the study.

    The researchers stumbled upon this discovery by accident. Two years ago, they had succeeded in describing how a mutation in mouse ATG16L1 wreaked havoc in a type of cell that inhabits the lining of the small intestine. These so-called Paneth cells are involved in mucosal immunity and secrete antimicrobial proteins. But in mice that carry the mutation, the cells grow abnormally and malfunction, similar to what's observed in human Crohn's patients with mutations in the same gene.

    But then, in early 2009, the mutant mouse colonies with the abnormal Paneth cells were moved to a new super-sterile facility. To the researchers' surprise, the mutant mice that grew up in the new facility had normal-looking, healthy Paneth cells. It was as if the mice didn't carry the mutation at all. This led them to believe that something other than genetics was at play.

    Enter the murine norovirus -- a family of small, RNA viruses discovered by Virgin in 2003. The viruses are practically found in almost all mouse facilities except the new one, which was designed expressly to keep them out.

    Sure enough, when the researchers fed mutant mice different viral strains, they found that after exposure to one strain known as CR6, the Paneth cells transformed from healthy to abnormal.

    This goes back to what doctors have observed for years. "It is not uncommon to find that inflammatory bowel disease follows some sort of gastric infection in a clinical setting," Stappenbeck explained. "So the connection between the disease and an infectious process has been around for a while."

    To explore this further, Stappenbeck and his team compared gene expression in mutant versus normal mice that are either infected or uninfected with the norovirus.

    They found that, when exposed to CR6 norovirus, the same set of genes that are down-regulated in normal mice are up-regulated in the mutant mice. As a result, in mutants, the Paneth cells are unable to secrete antimicrobial proteins -- leaving the microbe population in the gut unchecked.

    In this perturbed state, an additional disruption of the intestinal tract could result in chaos. This is precisely what happened when the mutant mice with the viral infection were fed the toxic chemical, dextran sodium sulfate. This additional "environmental hit," which basically pokes holes into the intestinal lining, set off a cascade of events that resulted in a full-blown inflammatory bowel disease that displayed many of the hallmarks of human Crohn's disease.

    "So really there were three environmental factors that were working together with the mutation: the viral infection, the composition of the microbiota (presumably induced by the viral infection), and a very specific inflammatory hit on the [intestinal lining]," Blumberg said.

    What's more, Stappenbeck found that by treating the mice with a wide spectrum of antibiotics -- in effect killing the intestinal microbes -- the disease state was eliminated.

    "This is a virally triggered [disease] that can be treated with antibiotics, which I think is really interesting," Stappenbeck said. "Normally viruses aren't susceptible to antibiotics, but because this [disease], which is triggered by a virus, requires the presence of normal microbes in the gut, you can stop it by wiping them out."

    The next step, Stappenbeck said, is to determine if there are human viruses that can trigger Crohn's. If so, it would explain why 50 percent of people with European ancestry carry the faulty ATG16L1 gene, but only a small fraction are affected. It might also explain why sometimes animal models carrying human susceptibility genes, but without their triggers, don't develop the disease.

    The paper "sort of opens a Pandora's box that makes interrogating the gene-environment interactions in this and other complex diseases much more complex," Blumberg said.

    Read more: Gene + virus + injury = disease? - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57509/#ixzz0roDiDOZZ
  4. Rita

    Rita Senior Member

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    I think the most important thing is that this study could be fairly applied to the case of CFS.We need to know the chemical, because we know the genetics and the virus that causes CFS.Perhaps its heavy metals.
  5. thegodofpleasure

    thegodofpleasure Player in a Greek Tragedy

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    Matlock, Derbyshire, Uk
    Article in Science Now "Recipe for Disease: A Gene and a Virus"

    This recent research, conducted by immunologist Thaddeus Stappenbeck and virologist Herbert Virgin of Washington University School of Medicine in St. Louis appears to link environmental factors with genetic predisposition, to the development of chronic illness.

    http://news.sciencemag.org/sciencenow/2010/06/recipe-for-disease-a-gene-and-a-.html

    Is this perhaps, a model for how we get ill, following infection with XMRV ?

    Thinking about it a bit further .........

    If you combine the work of the WPI on XMRV, with that of Dr. Kerr on gene SNP's and add in Dr. Chia's discoveries on enterovirus infections in ME/CFS

    ............then it seems to me that you have the same sort of viral infection + genetic predispositon + environmental mix that is described for the onset of Crohn's disease in a specific set of patients.

    I think that this theory also has the potential to explain the diverse range of sub-types seen within ME/CFS.

    TGOP
  6. ukxmrv

    ukxmrv Senior Member

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    Dr Kerr isn't working on SNP's - he's doing gene expression.

    Dr Peterson was asked about SNP's at one of the Invest in ME conferences and said that he wasn't seeing any links. However, that was pre-XMV announcement and further research could be in the pipeline.

    Dr Cheney said that he sees people with the MTHR mutation and Dr Yasko does a test for these sort of SNPS do it could be something along those lines maybe?

    XMRV+ (and with MTHFR mutation)
  7. Kate_UK

    Kate_UK Senior Member

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    My notes from Dr Kerr's talk at the last IiME conference say something about showing SNPs can be used to predict subtypes, however it is quite possible my notes are wrong.
  8. ukxmrv

    ukxmrv Senior Member

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    Was that from the questions Kate? Was he not asked and said no or don't know?

    His publlshed research is not on SNPS
  9. Kate_UK

    Kate_UK Senior Member

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    ukxmrv, sorry, I can't remember. My notes just say "subtype - predictive test, the 8 subtypes loosely clustered, showing SNPs can be used to predict subtypes".
  10. Gemini

    Gemini Senior Member

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    This Crohn's study was posted yesterday by Rita in "Other Health News & Research."
    Can someone combine the threads?

    Gemini
  11. thegodofpleasure

    thegodofpleasure Player in a Greek Tragedy

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    Dr Jonathan Kerr is definitely working on gene SNP's

    According to this profile of him http://www.meresearch.org.uk/research/projects/genesnps.html - Dr Kerr is working on gene SNP's

    TGOP
  12. taniaaust1

    taniaaust1 Senior Member

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    Sth Australia
    or it could be XMRV + methylation cycle problems (to which MTHFR morphism is only one of many, I myself have that polymorphism). I personally think the whole CFIDS thing is larger than just having XMRV but something to do with our genetics too.
  13. amstanley

    amstanley Guest

    ScienceNow Blog Story on Virus + Genetic Component = Disease

    Think XMRV and CFS or Autism and read this carefully.
    Notice any similiarities in the disease model described?
    Thought you might...

    Recipe for Disease: A Gene and a Virus - ScienceNOW


    Many of us carry genes for diseases that we'll never get. Take Crohn's disease, an autoimmune disorder that attacks the digestive system: Well over half the population harbors at least one genetic variant linked to Crohn's, but just a fraction of them currently have it. Scientists have known for a long time that environmental triggers help explain this discrepancy, but they don't know exactly how. Now, a chance discovery in mice shows that when animals with a particular Crohn's gene are exposed to a specific virus, they develop features similar to those in people with the diseasethe first time scientists have noted that genes and environment have intersected in this way in Crohn's. Scientists hope that the finding is just the beginning of many that will show how genes and environment combine in specific ways to produce all sorts of chronic diseases.

    The finding was a lucky break. Immunologist Thaddeus Stappenbeck and virologist Herbert Virgin of Washington University School of Medicine in St. Louis were moving their mouse colony to a superclean facility to keep the animals free of viruses that often afflict lab mice. The duo and colleagues had been working with mice who carried a gene called ATG16L1, which raises the risk of Crohn's disease in people. When the mice were moved, they no longer showed abnormalities in their intestinal cells. "There has to be an environmental trigger present in one facility but not the other," Virgin says he thought at the time.

    The researchers immediately homed in on a suspect: a virus that Virgin had discovered and reported in Nature 7 years ago called murine norovirus. Noroviruses are common in people, too, for whom they cause gastrointestinal upset. One of the most famous is the Norwalk virus, which commonly sickens people in close quarters, such as on cruise ships. For years, gastroenterologists have noticed that patients coming to them with newly diagnosed Crohn's disease had often suffered some sort of stomach virus recently.

    To test whether murine norovirus, which wasn't present in the "clean" facility, could explain the difference in their mice, the researchers infected the ATG16L1 mice with a particular strain of murine norovirus, called MNV CR6. After 7 days, inflammation showed up in a type of intestinal cell called Paneth cellsthe same abnormalities the mice had carried in their earlier, more germ-laden home. The inflammation is very similar to what's seen in patients with Crohn's disease in these same cells. Another strain of norovirus didn't have this effect, and the ATG16L1 mice stayed healthy.

    Scientists have long believed that in addition to genetics and viral exposure, Crohn's disease is driven partly by an abnormal balance of bacteria in the gut. Virgin, Stappenbeck, and their colleagues approximated this by taking ATG16L1 mice that had already been exposed to the norovirusso they were destined to suffer some intestinal problemsand fed them a solution that injures the intestines further. In otherwise healthy mice, the solution induced ulcers, which was expected. In the affected mice, the injection led to even more features that looked like Crohn's, including inflammation through the wall of the colon, the team reports in tomorrow's issue of Cell.

    R. Balfour Sartor, a gastroenterologist at the University of North Carolina, Chapel Hill, and chief medical adviser to the Crohn's and Colitis Foundation of America in New York City, says the work could help explain why the majority of people who have genes for Crohn's don't develop the disease. It shows that many factors are necessary to induce Crohn's, he says, but not one is sufficient all on its own.

    Still, much work remains to be done to determine how applicable the findings are to people, says Sartor. He'd also like to know whether other viruses, in the presence of ATG16L1, can have the same effectand whether other Crohn's genes combined with this norovirus do, too.

    Stappenbeck says that another big mystery is the mechanismhow exactly this norovirus combines with this particular gene to produce gut abnormalities. He and Virgin also plan to start looking at humans with Crohn's disease to see what viruses they may have been exposed to.
  14. ukxmrv

    ukxmrv Senior Member

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    Thank you GOP and Kate.

    All my apologies of missing that!!

    So glad to see that Dr Kerr is on the case.
  15. Gemini

    Gemini Senior Member

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    Dr. Klimas agrees... Dr. William Scott in her lab is studying the Genomics of ME/CFS (video):

    http://cfsknowledgecenter.com/expert-assistance.php

    She's very excited, plans to run "whole genome" scans to pick up all DNA-- human, viral, etc. in patients,

    Gemini
  16. kurt

    kurt Senior Member

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    That could match the pattern of post-viral CFS cases.

    Here is another article on this finding:

    Absolutely fascinating. Maybe over the next few years as full genomic profile costs continue to drop, we will have some answers regarding CFS genes. We already do know so much about viruses involved, and about some of the genes. Time to connect the dots...
  17. Dolphin

    Dolphin Senior Member

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    I can see where ukxmrv was coming from. Most of Dr. Kerr's published work hasn't been on SNPs but even some doctors were getting confused (and so confusing others). Some of this was called genetic work, but it really wasn't about hereditary factors (although hereditary factors can play a part in all abnormalities including gene expression).

    But he has been moving into the area of SNPs. I think in recent years it has been easier to test for lots of SNPs together just as around a decade ago it became easier to test for lots of gene expression together.

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