The study by the University of Edinburgh has found that genes responsible for Crohn’s disease are linked with other conditions including breast and prostate cancer, Hodgkin’s lymphoma, high cholesterol and obesity.
Knowing how diseases are genetically connected could aid efforts to develop medicines and potential side-effects could be predicted and avoided.
So what happened? The authors posit that the 503F allele was selectively favored at some point in the past, and flanking it were the Crohn’s disease risk elevating variants of IRF1 and IL5. All things equal it is best not to have a risk for this disease, but all things are not equal. If there was a strong enough selective pressure on the target, 503F, then the downsides of the fact that it came as a “total package” with some deleterious alleles would be irrelevant. Over a long enough evolutionary time the deleterious alleles would be purified through negative selection because recombination does break apart associations, but there’s a lot of reality which consists of being between beginnings and ends.
Saw an article about a new study that found a specific link between a gene mutation and virus that caused Crohn's Disease in mice. The study found that mice that had a gene variant linked to Crohn's Disease only developed Crohn's symptoms when they were infected by a specific, common norovirus called MNV.Two years ago, the researchers at Washington University School of Medicine in St. Louis and others discovered that mice with an ATG16L1 gene variant associated with Crohn's disease in humans develop similar abnormalities in gut immune cells called Paneth cells. But the mutation alone wasn't enough to trigger Crohn's disease.
In a routine screening, the team later found that mice with the gene variant developed Crohn's disease symptoms within seven days after exposure to the MNV norovirus.
The study appears in the June 25 issue of the journal Cell.
It's been suspected that autoimmune and other diseases might be influenced by viral infections, but "this is the first really clear indication of a disease caused by a susceptibility gene and a specific virus," study co-leader Thaddeus Stappenback said in a journal news release.
The list of health issues that are being categorized as autoimmune diseases are just stacking up! Saw an article a couple weeks ago that alopecia areata, a disease that causes hair loss and baldness, was caused by an autoimmune response. And a more recent article confirmed that narcolepsy is also autoimmune.
Saw a really interesting article in Scientific American about a study regarding a link between a specific strain of bacteria and rheumatoid arthritis (RA) in mice. The study found that the introduction of a single type of bacteria could increase the amount of IL-17 (interleukin 17), a protein that signals the immune system to cause inflammation, in the mouse. The "friendly" bacteria that causes this accelerated the onset of arthritis in the mice. The mice were selected to already be genetically predisposed to having arthritis, so all mice in the study developed arthritis. But the mice that were given the bacteria developed RA much more quickly.Mathis emphasized that one should not take away from these mouse studies "that mice or humans can 'catch' an autoimmune disease or arthritis," she says. She added that the better way to think about it is that individuals have varying degrees of genetic susceptibility, and when exposed to certain environmental factors may then go on to develop disease. "It's really an interaction between genetics and environment," Mathis says.
Saw a couple articles (BusinessWeek, Wired.com, ScienceNews) commenting on a story in Nature about a study that found that variations in a single gene could result in different types of autoimmune diseases, including Crohn's Disease and diabetes.The gene in question encodes an enzyme called sialic acid acetylesterase or SIAE, which regulates the activity of the immune system’s antibody-producing B cells. About 2 percent to 3 percent of people with autoimmune disorders have defects in the enzyme that allow B cells to run amok and make antibodies that attack the body, a team led by Shiv Pillai of Massachusetts General Hospital in Charlestown and Harvard Medical School reports online June 16 inNature.
“It’s a seminal paper because it is so applicable to a wide variety of autoimmune diseases, says Judy Cho, a Yale geneticist not associated with the study. The finding suggests that enhancing the enzyme’s activity could help treat disease in people with autoimmune disorders.
I came across a really interesting article regarding a possible causative mechanism for multiple sclerosis (MS). As you most likely know, MS is an autoimmune disease (similar to IBD and Crohn's) where immune cells misguidedly attack the body's own cells. In the case of MS, the body is attacking the protective sheath around major nerves. In the case of IBD, the body is attacking your intestinal tissue.The authors explained that it's possible that multiple viruses could influence susceptibility to multiple sclerosis. The ability of any particular virus to contribute to the disease could depend on an individual's own repertoire of other predisposing genes, exposure to other predisposing environmental factors, and the random chance that T cells had been generated that recognize a myelin protein and a pathogen.
Receptors on T cells are randomly generated during their development. This observation helps explain why multiple sclerosis is partly a matter of chance. Some people with a genetic predisposition and environmental exposure develop the disease, while others with similar genetic predisposition and environmental exposure do not.
The study, was conducted to estimate the likelihood that three particular genetic variants in the NOD2/CARD15 gene are related to the risk Crohn disease in the general population.
The population-based study genotyped 43 596 Danish people followed between January 1976 and July 2007. Using a logistic regression model (used to predict the probability of an occurrence) physicians estimated the risk of Crohn disease in the general population.
"Surprisingly, we found no statistically significant association between NOD2/CARD15 genetic variants and Crohn disease in either of the two general population studies that we analyzed, which suggests a low penetrance of the genetic variants in the European general population," write Dr. Børge G. Nordestgaard, Herlev Hospital, University of Copenhagen, Denmark and coauthors. (Penetrance is the degree to which the gene causes the disease.)
The authors conclude that the penetrance of NO2D/CARD15 genetic variants in relation to risk of Crohn for the Danish population was lower than might have been expected from previous European case-control studies. This should be considered when advising healthy individuals in whom these genetic variants are discovered.
In a related commentary http://www.cmaj.ca/embargo/cmaj100300.pdf, Dr. Katherine A. Siminovitch and coauthors write that these research findings reinforce the fact that common diseases have many causes and that in these diseases, the effect of any single gene variant on risk is usually small. This underscores the current challenge in realizing the potential of personalized medicine (use of an individual's specific information to select or optimize preventive care and therapy).
Researchers demonstrated that in a mouse model of colitis, Nlrp3 plays a pivotal role in keeping the intestinal tract intact, thus preventing further damage that occurs if intestinal bacteria leak into the body.Nlrp3 works by anchoring a large, multi-protein complex known as the Nlrp3 inflammasome where the messenger protein interleukin 18 (IL-18) is made.IL-18 belongs to a family of molecules known as cytokines, which shape the body's immune response. In this study, researchers showed IL-18 produced by the Nlrp3 inflammasome helped mice maintain healthy colon by triggering production of more epithelial cells to compensate for those damaged or destroyed by colitis."This paper provides the basis for more effective, potentially disease-modifying approaches to treatment," Kanneganti said.
"We have made a novel discovery," said Dr. Fayez K. Ghishan, professor and director of the Steele Center. "Based on our research, it appears that chronic inflammation of the gut causes Klotho to down-regulate – or ‘turn off' – contributing to premature-aging diseases such as osteopenia, osteoporosis and atherosclerosis, to name a few."
"We can now theorize that if you have an inflammatory process going on, like IBD or rheumatoid arthritis, for example, you are likely to develop symptoms of premature aging," Kiela said. "Our findings lay the foundation for future work related to the contribution of Klotho to chronic inflammatory diseases in human patients – and how to better treat these diseases."
One of the most promising treatments in this category is a drug called CM-AT made by a startup called Curemark. Dr. Joan Fallon, the company's founder and CEO, observed that many autistics show a strong preference for foods high in carbohydrates and low in protein. A diagnostic test revealed that some autistic children lack enzymes that digest protein. As a result, these children produce fewer of the essential amino acids that are the building blocks for brain development and neuroreception. Fallon believes this deficiency is linked to the most severe symptoms of autism, and she says an early observational study of CM-AT, an orally ingested powder that delivers protein-digesting protease, showed "significant improvements." Curemark is enrolling patients in phase III clinical trials at 10 to 12 sites—the largest autism trial to date.
I just read a really great paper ("Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn’s disease") that summarized recent literature on the role of Mycobacterium avium paratuberculosis (MAP) in Crohn's Disease. I've had several previous posts regarding MAP's potential role in Crohn's and IBD, but this paper was much more comprehensive and cited studies I had not heard of.MAP is the causative agent of Johne’s disease. It seems likely that chronic infection with MAP does occasionally occur in humans. MAP is widely present in our food chain and the DNA of this organism can be recovered from the intestine of CD patients. Studies have shown that a high percentage of subjects with CD are infected with MAP, though whether the association of this bacterium and CD is causal or coincidental is not known. Epidemiologists have gathered enough information to indicate an association between MAP and CD. Nonetheless, the role of MAP in CD etiology is not known, and may be determined from consistent results of studies using improved methods of isolation and detection of MAP bacilli and/or MAP-elicited immune responses in the host.
Based on their analyses, the researchers suggest autoimmune diseases fall into at least two different groups: one containing rheumatoid arthritis and ankylosing spondylitis and another containing multiple sclerosis and autoimmune thyroid disease.
Meanwhile, they reported, type 1 diabetes resembled both of the groups to a certain extent, sharing characteristics with autoimmune thyroid disease but not multiple sclerosis. Crohn's disease, on the other hand, did not cluster with either group.
It still wasn't clear, however, what caused the weakened immunity in the first place. So Segal's team focused on cells called macrophages, the immune system's whistle-blowers. In people with Crohn's disease, they found that macrophages secrete lower levels of cytokines, the chemicals that rally other immune cells to infection sites (Journal of Experimental Medicine, DOI: 10.1084/jem.20091683).
The team concluded that ineffectual rallying of immune cells in people with defective macrophages is what allows intestinal bacteria to run amok in the early stages of an infection, setting in motion the series of events that leads to Crohn's disease.
Just saw an article in the LA Times about how much you can trust new consumer DNA tests. The article highlights a recent experiment that compared the results of two of the leading vendors in this space, Navigenics and 23andMe. The experiment found that in some cases the two vendors conclusions about disease susceptibility was in agreement, but in others it was wildly different. The reason: each company uses different research studies to draw their conclusions. So, one might say that you have a 25% chance of developing Crohn's while the other says something higher. So although both companies do a great job of reading your DNA correctly, the determination of disease susceptibility is simply not a perfect science. In many cases, particularly those where definitive cause is unclear (like Crohn's), it's far from perfect and can generate very different results.
All humans have a CD39 gene. But some have a version of the gene linked to lower CD39 levels. Friedman and colleagues identified a genetic marker for low CD39 production. They then looked for this marker in 1,748 patients with Crohn's disease and in 2,936 people without IBD.
They found that the genetic marker was significantly more common in people with Crohn's disease. Moreover, people without IBD were more likely to carry two copies of the high-CD39 gene, while those with Crohn's disease were more likely to carry two copies of the low-CD39 gene.
Genetics are not destiny. Not everyone with the low-CD39 gene has or will have IBD. Even having two copies of the gene only increases a person's risk of Crohn's disease by 27%.
But since about 40% of whites of European ancestry carry at least one copy of the gene, its effects across the entire population should be quite large.
Dr. Scott’s results offer the first suggestions that T cells
Small lymph cells created in the thymus which orchestrate the immune system\'s response to infected or malignant cells. Also known as T lymphocytes. T cells in the immune systems of type 1 diabetics are also more likely to have adverse immune reactions to wheat. His results also suggest that such over-reaction is tied to genes associated with type 1 diabetes.
According to Dr. Scott, the research suggests that "people with certain genes may be more likely to develop an over-reaction to wheat and possibly other foods in the gut and this may tip the balance with the immune system and make the body more likely to develop other immune problems, such as type 1 diabetes.”
Dr. Scott adds that the immune system has to find "the perfect balance to defend the body against foreign invaders without hurting itself or over-reacting to the environment and this can be particularly challenging in the gut, where there is an abundance of food and bacteria.”
In side comments that accompany the paper, diabetes expert Dr. Mikael Knip of Finland suggest that the team's results "add to the accumulating concept that the gut is an active player in the diabetes disease process.”
I just saw a post from the Napa County Science News Examiner (thank Google Alerts for that) commenting on an upcoming research paper that will be published in the September issue of "Annals of the New York Academy of Sciences" regarding Vitamin D's role in auto-immune diseases. The post talks about a recent research paper that discusses why Vitamin D may be even more important for women than in men (and could also explain higher rates of auto-immune diseases in women). The paper found that women have a higher number of Vitamin D receptors in their body, in particular in the endometrial cells (lining of the uterus). When Vitamin D binds with these receptors, many genes are expressed that help kick-up the immune system.The key to how vitamin D plays its part is to understand what the VDR does. When the correct form of vitamin D (a form known as 1,25-D or calcitriol) binds to VDR, VDR then directly causes the expression of over 900 genes to occur. Two of the genes that are turned on produce proteins that are directly responsible for kicking the immune response into active mode. The reason for VDR in the endometrium is that it provides protection against infection for the developing fetus.Another key to the puzzle has been the growing evidence that bacteria may play a role in the development of autoimmune disease. If so, why wouldn’t women, who have more VDRs, be better off than men? The problem is that bacteria of various kinds can interfere with VDRs and prevent vitamin D from binding. If vitamin is unable to bind, then the immune response is disrupted. Not only is the immune system affected, but thyroid hormone problems can result too.
Although these results do not provide a clear path to treatment, “the potential role of persistent pathogens in autoimmune disease mandates reconsideration of the use of corticosteroids as a first-line treatment for many autoimmune diseases. Corticosteroids effectively reduce the ability of the immune system to respond to pathogens, including persistent microbiota, which is counterproductive to recovery.”
ISLAMABAD: Contrary to expectations, people with the inflammatory bowel condition Crohn’s disease are likely to have excessive levels of the active form of vitamin D in their blood, researchers have found. This is associated with low bone mineral density, they report.
Dr. Maria T. Abreu from the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center in Los Angeles led the study. She told Reuters Health, "Most doctors think that Crohn’s patients automatically have decreased vitamin D levels and encourage supplementation with vitamin D. We would like to urge doctors to check vitamin D levels before making that recommendation."
As Abreu’s team explains in the medical journal Gut, under certain circumstances too much active vitamin D can actually contribute to the breakdown of bone, leading to osteoporosis. The researchers found "inappropriately high" blood levels of the active form of vitamin D in 42 percent of the 138 people they studied with Crohn’s disease. This was true of only 7 percent of 29 patients with ulcerative colitis, another type of inflammatory bowel disease.
Also, the higher the blood levels of active vitamin D in Crohn’s patients, the lower was their bone density -- regardless of whether they were treated with steroids -- the investigators found. "We believe that high vitamin D levels are most likely a manifestation of the underlying gut inflammation," Abreu said. A high vitamin D level is "an additional risk factor predisposing to development of osteoporosis" for some Crohn’s disease patients, the team concludes. Treatment of the underlying inflammation, "may improve metabolic bone disease."
