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Identifying MS gene mutations could lead to personalised treatments(24/07/15)

Personalised medicine, often applied to treat cancer, may be possible for patients with multiple sclerosis as well. Certain patients respond differently to certain multiple sclerosis medications, such as interferon-β (IFNβ), and researchers at San Raffaele Scientific Institute in Milan may have an answer as to why.

The team, led by Federica Esposito, MD, PhD, found that multiple sclerosis patients with a specific mutation in the gene SLC9A9 have more frequent relapses despite treatment with IFNβ.

“A proportion of multiple sclerosis patients experience disease activity despite treatment,” wrote Dr Esposito, explaining the motivation behind the study.

“The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalised approach.”

To achieve this goal, the research team looked for associations between multiple sclerosis patient gene expression and response to treatment with IFNβ. The researchers’ findings, published in Annals of Neurology and entitled, “A Pharmacogenetic study Implicates SLC9a9 in Multiple Sclerosis Disease Activity,” demonstrated that a genetic mutation in the gene SLC9a9, namely the rs9828519G variant, can be used to predict how multiple sclerosis patients will respond to treatment.

“Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in multiple sclerosis subjects who are more likely to have relapses,” noted Dr Esposito. When the research team used patient-derived T cells to study the effects of SLC9A9 gene expression on IFN, they saw an increase in the pro-inflammatory molecule IFNγ.

The new information in this study may be able to screen multiple sclerosis patients for efficacious disease therapies. For example, if a patient carries a mutation in SLC9A9 that prevents its transcription into mRNA, that patient may not be well suited for IFNβ and may be a candidate for a different treatment option.

The idea is similar to that of MSPrecise, best described by an article published in Gene, MSPrecise: A Molecular Diagnostic Test For Multiple Sclerosis Using Next Generation Sequencing. This screen also finds mutations in DNA, specifically in cerebrospinal fluid-derived B cells that express a VH4 gene. Clinicians have shown it accurately identifies 84 per cent of patients who develop relapsing-remitting multiple sclerosis (RRMS). If used together, a clinician may be able to determine if an individual has RRMS via MSPrecise, then determine if IFNβ is a suitable treatment by testing for SLC9A9 mutations.

At present, currently approved multiple sclerosis therapies are developed to treat a wide range of patients and are tested on diverse patient populations in order to determine if they are relatively effective in treating the disease in across a broad clinical population. However, as the human DNA is decoded and gene mutations are better understood, the more possible it becomes to tailor future MS therapies to maximise therapeutic value for each individual patient.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (24/07/15)

Gene that "triggers" multiple sclerosis identified(18/06/15)

New research identifies a pivotal gene in multiple sclerosis, linking it to the most important genetic factor that drives the condition.

The human leukocyte antigen class II proteins (HLA-II) is the strongest genetic factor that influences multiple sclerosis. It helps the immune system distinguish the body’s own proteins from foreign proteins, and disturbing this system increases the chances of auto-immune disease. Researchers from The Netherlands and Qatar have discovered how mutation of a single base in the CLEC16A gene interferes with the normal function of HLA-II.

The mutation in CLEC16A results in a faulty HLA-II system, generating blind immune cells that are unable to differentiate pathogen-derived proteins (also known as antigens) from the body’s own proteins. When such blind immune cells escape to the brain, they destroy nerve-insulating myelin, resulting in multiple sclerosis.

The scientists found that silencing the activity of the CLEC16A gene in specific antigen-presenting cells disrupted the ability of HLA-II to display antigens on the cell membrane. Next, they identified that the levels of inactive CLEC16A protein in peripheral blood mononuclear cells of multiple sclerosis patients were two times higher than those of healthy individuals, indicating that CLEC16A has a role in the disease.

“In the future, immunology will continue to unravel what all the risk genes such as CLEC16A really do in the complex adaptive immune system, hopefully aiding the development of new drugs that could interfere with relevant disease-causing pathways,” says lead author Rogier Hintzen from the University Medical Centre, Rotterdam.

Source: Nature Middle East © 2015 Nature Publishing Group (18/06/15)

Researcher improves methodology for predicting genetic ‘mutations’(16/06/15)

Researchers around the world have sequenced the genomes of patients living with from common, multi-gene diseases, looking for common mutations in their control regions. However these studies produce hundreds of mutations, many of which prove to be benign.

Now a research team led by associate professor of biomedical engineering, Michael Beer, have generated a new computational formula for predicting which mutations in control regions will wreak the most havoc. Their research has been published in Nature Genetics.

Their focus was on finding genetic control regions in stretches of DNA positioned near most genes. These regions act like dimmer switches which control the amount of each protein produced. Mutations in control regions generally have more subtle effects than mutations in genes themselves, but they can contribute to common, genetically complex, chronic diseases such as diabetes.

Beer’s team first “trained” their computer program to recognise and measure DNase sensitivity in susceptible genetic control regions. DNase is an enzyme that cuts DNA wherever it is not tightly wound. The openness of particular sequences of DNA varies among different types of cells and only control regions with open DNA can be active. How vulnerable certain stretches of DNA are to DNase is therefore an indication of which control regions are important in a given cell type.

They then computationally simulated “mutating” every DNA letter in turn and recalculated each section’s contribution to DNAse sensitivity. The larger the change in sensitivity after a given mutation, the more likely it is that that mutation will effect gene activity levels in the cell, Beer says.

The team compared these computer predictions to the known effects of some mutations, and to the predictions made by alternative programs. When the programs’ “rules” were set to be equally thorough in their searches, Beer’s program was 56 percent accurate — 10 times more accurate than the next best program.

Beer worked with Andrew McCallion, PhD an associate professor at the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine to further test the computational formula to predict the impact of mutations in the control regions for two pigment-related genes in mouse skin cells. They found that there was a strong correlation between the program’s prediction and the actual change experienced by the cells.

Dr. Beer and his team also tested their formula in mouse and human liver cells, and in human leukemia cells, and got similar results. They also tested their formula on three control region mutations already known to affect cholesterol levels, hemoglobin levels and prostate cancer. Again they found that these mutations drew higher computer scores than other mutations in the same control regions.

Finally, the team examined the control regions for T helper cells, a type of immune cell that can contribute to autoimmune diseases. Their calculations identified 15 different control region mutations associated with nine different immune system disorders from allergies to multiple sclerosis and Crohn’s disease. The research honed in on the exact genetic mutation that mattered. Beer says, “The next step is to test gene activity levels in patients and find out if our predictions were right. If so, it should help us determine how the activity is being perturbed and how we can fix it.”

This computational analysis can be repeated on many other diseases to provide timesaving insights for each.

Other authors of the report include Dongwon Lee, David Gorkin, and Maggie Baker, of the Johns Hopkins University School of Medicine, and Benjamin Strober and Alessandro Asoni who contributed to the project while undergraduates in the Department of Biomedical Engineering.

Source: Johns Hopkins Biomedical Engineering © 2015 Johns Hopkins Department of Biomedical Engineering (16/06/15)

Gene linked to interferon-beta treatment(18/05/15)

A new study led by investigators at Brigham and Womens Hospital (BWH) reports the discovery of a genetic variant associated with a patients likelihood of responding to interferon-beta, one of the medications used in treating multiple sclerosis.

Published in the Annals of Neurology, the study also presents evidence that the affected gene, SLC9A9, may have a broader role in regulating the development and activity of certain immune cells that play important roles in inflammatory diseases like MS.

The variant most predictive of whether or not a patient would respond to the drug was found in the gene SLC9A9.

"This study highlights the fact that genetic variation has a role in the course of a patient's MS, but that this role is modest and will require much larger studies to be understood in detail," said Philip De Jager, MD, PhD, who directs the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH.

A large, ongoing study of MS patients called CLIMB, based out of the Partners Multiple Sclerosis Center, was integral to the current work and will continue to follow patients over the course of treatment to identify predictors of future disease course and the effectiveness of treatments.

Additional support was provided by the National MS Society, Fondazione Italiana Sclerosi, the French MS society Association pour la recherche sur la sclerose en plaques, the Club francophone de la SEP, and the Reseau francais pour la genetique de la SEP.

De Jager is a recipient of the prestigious Harry Weaver Neuroscience Scholar of the National MS Society.

Source: Demanjo Copyright © Demanjo 2015 (18/05/15)

Genetic risk factor uncovered(05/03/15)

Researchers at the University of Illinois at Chicago have identified a genetic variation that in women significantly increases their risk of developing multiple sclerosis. The report is published in the journal ASN Neuro.

The variant occurs almost twice as often among women with MS as in women without the disease, making it "one of the strongest genetic risk factors for MS discovered to date," said senior author Doug Feinstein, professor of anesthesiology at UIC and research biologist at the Jesse Brown VA Medical Center.

Feinstein and his colleagues were able to test three sisters among a group of five siblings between the ages of 23 and 26, all diagnosed with MS. They found the variant in all three they tested.

What they found was a genetic change known as a single nucleotide polymorphism, or SNP - a change in a single base-pair of the DNA - in a gene called STK11, which plays a role in tumor suppression and is believed to have several roles in brain function.

Genetic factors are known to influence the risk of developing MS. The UIC researchers were led to this variant thanks to a woman participating in another study at UIC. In a casual conversation, the woman told study coordinator Anne Boullerne that she and her four siblings - three sisters, including twins, and a brother - all had multiple sclerosis.

"This is an extremely rare occurrence," said Boullerne, who is research assistant professor of anesthesiology and lead author on the paper. She said she could find no published studies with five siblings with multiple sclerosis.

"I was immediately interested in the possibility of a genetic study of the family because all five siblings - an entire generation - are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease."

The woman also described among her sisters and the women on her mother's side of the family a prevalence of diseases associated with Peutz-Jeghers syndrome, a rare genetic disorder caused by mutations in the STK11 gene and characterized by an increased risk for certain cancers, including breast, ovary and colon cancers.

A literature search by Feinstein uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the central nervous system - a defining characteristic of MS.

The woman consented to a complete DNA-sequencing of her genome. Boullerne took a close look at the STK11 gene, where she discovered the SNP. She next obtained consent to sequence the genomes of two of the woman's sisters and found they also carried the same SNP.

To determine if the SNP could be a contributing factor to the siblings' multiple sclerosis, the researchers screened DNA samples from 1,400 people - 750 with MS and 650 without - provided by Jorge Oksenberg at the University of California, San Francisco, who is a leading expert on the genetics of MS. They found that the SNP was 1.7 times as prevalent in women with MS as in women without the disease, making it one of the highest known genetic risk factors for MS.

Based on their analysis, the researchers estimate that the STK11 SNP is present in about 7 percent of the general population. But because far fewer people develop MS, other genetic or non-genetic factors must play a role in the development of the disease, Feinstein said.

Feinstein and Boullerne plan to continue their hunt for other genetic factors that may contribute to MS among the five siblings and possibly their parents. They will also investigate the function of the STK11 gene in the lab, which could reveal molecular pathways involved in multiple sclerosis.

Source: Medical Xpress © Medical Xpress 2011-2015, Science X network (05/03/15)

Unraveling the mystery of how our immune system turns on itself(05/12/14)

What role does our genetic makeup play in autoimmune diseases – diseases like lupus and multiple sclerosis wherein the body’s own immune system turns on it? That question has plagued researchers for decades. However, a new gene mutation has been discovered that could help scientists map an autoimmune disease in the body and find out how the immune system is inappropriately triggered to attack itself.

Researchers in a new study at the University of Edinburgh have honed in on five of 89 independent variations in human genetics that are believed to be responsible for autoimmune conditions, from celiac disease and multiple sclerosis to rheumatoid arthritis and asthma. Understanding how these mechanisms work could help scientists to develop new treatments.

The team found that a mutation in the ADAR1 gene causes a defect in an “alarm system” in cells that normally protects the body from viruses and other infections by triggering the body’s immune system to fight. The mutation causes this alarm system to be tripped by the cell’s own molecules, causing the immune system to attack – the uniting trait of all autoimmune diseases.

The ADAR1 mutation and the others identified by the researchers together helped reveal the system that helps the body to differentiate between normal RNA and RNA from foreign organisms. The exact problem with this mechanism that characterizes autoimmune disorders differs for each, as the body’s way of attacking itself is unique and presents no two symptoms that are exactly alike, even within families.

There are more than 80 types of autoimmune diseases affecting 5-8 percent of the American population. There are no obvious patterns in autoimmune disease; individuals of any age and sex may be affected, making the process of pin-pointing important genes extremely difficult.

Though autoimmune diseases vary wildly in their specifics, a family history of autoimmune disorders can indicate a genetic predisposition that may increase the risk to develop an autoimmune disease. This risk persists even when dealing with different autoimmune diseases. In a predisposed family, a woman may have rheumatoid arthritis and one of her siblings may develop lupus. While diseases can be passed down from parent to child, it doesn’t automatically mean someone will get the same disorders their family members suffer from. The exact nature of the immune response and how the body deals with it varies from case to case.

Though identifying genetic common ground is essential to a better understanding and treatment of autoimmune diseases, environmental factors can also play an important role in triggering the onset of disease. A few such triggers have been identified, including several drugs that are associated with some forms of lupus, thrombocytopenia, and hemolytic anemia. Sometimes infections can trigger an autoimmune disease, such as rheumatic fever caused by a streptococcal infection and Guillain-Barre syndrome caused by chlamydia. In addition, a great deal of circumstantial evidence suggests that viruses may play a role in initiating some autoimmune diseases. Despite these known triggers, most cases of autoimmune disease cannot be linked to clear evidence of a particular environmental trigger.

The new ability the researchers found to associate specific genetic variants with autoimmune disease broadly and to probe will enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen fired-up immune responses. Finding the ADAR1 mutation is a huge step toward learning more about autoimmune diseases and what exactly they do to the human body when active. Mapping the relevant mutations and their chemical signatures in the body helps reveal the exact mechanisms by which autoimmune diseases occur and cause harm – hopefully providing new targets for doctors trying to treat these stubborn and pernicious disease.

Source: The Genetic Literacy Project. © 2014 The Genetic Literacy Project (05/12/14)

Does multiple sclerosis stem from immune system and not the nervous system?(14/11/14)

A multifaceted team of researchers developed a new mathematical formula to scour existing DNA databases in order to determine why inherited DNA variations contribute to disease. The sequencing techniques they developed examined epigenetic characteristics of specialised immune cells.

Previously, the researchers had used a similar tool to study 21 different autoimmune diseases, and they were able to apply that method to the current project.

The researchers probed 39 genome-wide association studies (GWAS) – which each enlist thousands of participants – to identify DNA blocks implicated in genetic factors for diseases. GWAS rarely point to altered proteins, however. The researchers believe this is because only a few protein-encoding gene variants with these DNA codes have been investigated, let alone associated with autoimmune disease.

Investigators found the presence of specific gene variants differ among autoimmune diseases, which can further alter the functional ability of the immune system. This remained true even though the genetic variants are not within genes.

The majority of DNA changes related to autoimmune diseases occurred in the section of DNA known as “enhancers.” The enhancers of DNA – which is typically shaped in stringy molecules – allow DNA to fold so the various proteins can interact with each other. The enhancers also allow the bending of DNA to activate switches that can turn on specific genes. The enhancers the researchers identified as essential to DNA interaction had not been previously thought to have any functional role.

“Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology,” Alex Marson, MD, PhD, the corresponding author for the study, said in a press release.

After combing through data collected about DNA patterns, the researchers determined T helpers, a type of immune cell, may be a response to stimuli that increase the risk of autoimmune diseases. The researchers believe MS therefore stems from the immune system, and not from genetic variants associated with the nervous system.

“This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” David A. Hafler, MD, co-first author of the study, continued in the press release. He went on to explain that the immune system plays a primary role in MS, and is almost certainly an autoimmune disease.

The researchers hope these findings can ultimately lead to better diagnosis and improved treatments.

Source: HCPLive © Health Care Professionals 2014 (14/11/14)

New DNA software may improve MS diagnosis and treatment(31/10/14)

Researchers from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine recently developed a software tool that helps researchers understand the complex genetic origins of many autoimmune diseases and, ultimately, to better diagnose and treat them. The study was published yesterday in Nature.

One in every twelve Americans are affected with autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes, rheumatoid arthritis, and asthma. What happens in these kinds of diseases is that the immune system begins to attack the body’s own cells and tissues. This new study connects insights into genetics with the origins of these diseases — a connection that the tool’s creators believe will serve as a key asset for diagnosing and treating autoimmune diseases like MS.

The researchers developed a mathematical tool to more intensively probe existing DNA databases, which in turn has allowed them to discover that certain DNA variations contribute to the development of diseases and, if inherited, can signify a higher predisposition for becoming sick.

Through their method, the researchers analyzed data from previous studies regarding 21 autoimmune diseases, and thoroughly examined their scientific fundamentals. From this analysis, they found specific immune cells that are actually responsible for the diseases.

Data from 39 large-scale studies called GWAS, the genome-wide association studies, was analyzed. Many GWAS analyses have been conducted, and each one enlisted a large number of participants allowing researchers to identify large blocks of DNA within the human genome and within each genetic variant related to a disease that might represent risk factors. Until now, the GWAS examination has rarely pointed to altered proteins, and few protein-encoding gene variants in a large amount of DNA evidence like this one were associated with the diseases under investigation.

The genetic risks identified through GWAS studies suggest that the answer may reside in DNA variations that are not within genes. Therefore, medical benefits have emerged from large-scale studies of human genetic variations conducted in the wake of the Human Genome Project.

Researchers figured that specific genetic variants in several autoimmune diseases can change patterns of the genes’ activity in ways that affect immune system functions. This study focused on “epigenetic” characteristics in which genes’ activity is affected, but the DNA sequences of the affected genes remain untouched. As a result, these variations in DNA do not occur in genes’ zones; the majority occur in functional DNA fragments known as “enhancers.”

DNA can bend back by supporting itself in a chromosome’s structural proteins, and a piece of DNA, usually long and stringy, can interact with another strand. Enhancers fold in like this to bind to DNA switches and activate genes. The enhancers identified in this study and that play a role in the autoimmune diseases were DNA sequences different from DNA-sequence, which were previously thought to be crucial for enhancers to work and are a novelty, as they function as sequences that are actually functional.

Alex Marson, MD, PhD, UCSF Sandler Faculty Fellow and the author of the study, said in a press release: “Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology.”

Mapping enhancers in specialized immune cells and tracking patterns of altered gene activation in GWAS studies allowed the researchers to associate this phenomena with the respective immune diseases. Many of them were found to be related to immune cells known as “T helpers.” The study suggests that genetic variation may be triggering a response from these immune cells to stimuli within their surroundings to increase the risk of autoimmunity.

Marson and his team link the cause of MS to the immune system and not to the genetic variations concerning the nervous system. Results show that MS is an autoimmune disease: “This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” said David A. Hafler, MD, professor of neurology and immunobiology, and chair of the Department of Neurology at Yale and Marson’s collaborator.

These new findings will ultimately “enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen aberrantly fired-up immune responses,” cited from the UCSF press release.

The major funding for this study came from the National Institutes of Health and the National Multiple Sclerosis Society, and through it, Marson intends to understand how these newly identified DNA variants in enhancers affect cells and cause diseases, and how these consequences can be mitigated through DNA manipulation.

Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (31/10/14)

New gene variants may relate to MS susceptibility(03/10/14)

Approximately 110 multiple genetic variations were previously identified by genome-wide association studies (GWAS) to be associated with Multiple Sclerosis (MS). Now, that number has increased, with more than 159 genetic variants identified, thanks to new research presented by Philip De Jager, M.D., of Brigham and Women’s Hospital, Harvard Medical School and the International MS Genetics Consortium at the ACTRIMS-ECTRIMS conference in Boston.

The team led by Dr. De Jager performed the first comprehensive meta-analysis of existing MS-GWAS, spanning approximately 14,000 individuals with the disease. The researchers identified unknown genetic variants, and further studies involving 2,000 individuals led to confirmation of 48 new variants — for now.

With the confirmed identification of these new genetic variants, the team proposed to understand how the variants relate to MS susceptibility. Dr. De Jager noted, “the majority of the MS genes seemed to be related to immune function and expressed on immune cells.” The authors hypothesized the new variants could be related with alterations to brain function. To test their hypothesis, they examined the newly genetic variants in older, MS-free postmortem frontal lobes’ tissues. “[This is] exciting because there are at least some disease effects that may be related to alteration of gene expression inside the brain,” commented the author. Since the analysis was performed with the whole tissue, at the moment the authors can’t confirm the source cell type for these genes, as Dr De Jager noted, “Some of these changes may be driven by changes in the brain’s immune cells like changes in the microglia.”

Notably, Dr. De Jager highlighted how certain genome regions harbor multiple different variants that impact the risk for MS. Hence, to develop reliable predictive tests for MS, it is crucial to study each of these variants and fully understand their functional impact on MS.

The current study explains less than half of the heritability of MS, so Dr. De Jagers’ team and the International MS Genetics Consortium are committed to identify more genetic variants for MS susceptibility and to study it thoroughly.

Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (03/10/14)