DioGenix, Inc. announced today new data supporting the clinical validation of MSPrecise®, its proprietary next-generation sequencing (NGS) assay for the identification of patients with multiple sclerosis (MS) at first clinical presentation. The prospective study met its primary endpoint by demonstrating the ability of MSPrecise to diagnose patients with MS. The test performed consistently with previous clinical studies, having a specificity of 82% while maintaining sensitivity comparable to what has been published for the current standard of care (p= .0027).
Over 200 subjects being evaluated for non-specific neurological symptoms that could be MS, were enrolled in the prospective, blinded clinical trial that validated the performance of MSPrecise. Each subject was undergoing a comprehensive evaluation using the current standard of care for imaging of the central nervous system (CNS) and analysis of their cerebral spinal fluid and blood. This study compared the results of MSPrecise DNA mutational analysis with a consensus diagnosis made by a panel of independent neurologists chosen for their significant clinical experience in diagnosing and treating MS. The MSPrecise interpretive scoring system provides a simple scaled score to the neurologist who differentiates patients with MS from those with other similarly presenting neurological diseases. Thirteen MS clinical centers of excellence participated in the trial – believed to be the largest prospective diagnostic study of its kind in MS – with over 20 thought-leading clinicians consenting subjects. Results from this study will be submitted for peer review.
"MSPrecise interrogates key genes involved in the immune system of patients being evaluated for MS. The growing body of evidence indicates this next-generation sequencing assay may advance our efforts to more accurately diagnose patients with MS or other immune-mediated neurological disease," said Elliot M. Frohman, M.D., Ph.D., FAAN, Professor of Neurology & Ophthalmology and Director, MS Program and Clinical Center for MS at The University of Texas Southwestern Medical Center.
These results are consistent with two prior DioGenix studies that compared MSPrecise to published performance data for the oligoclonal banding (OCB) test and experimental controls. In a previous, mainly retrospective verification study, MSPrecise demonstrated a clear improvement in the ability to classify early-stage MS patients from those with other similarly presenting neurological diseases in comparison to OCB analysis.
"DioGenix continues to clearly demonstrate the power of MSPrecise to accurately identify patients with neurodegenerative diseases like MS. MSPrecise should offer neurologists greater insight into early disease events by exploiting the incredible biological resolution provided by next-generation sequencing. As we are able to now more accurately measure these key early biological changes we believe we can help inform more appropriate courses of treatment for individuals who suffer from these types of immune-mediated diseases," said Larry Tiffany, President and CEO of DioGenix. "The positive results of our validation study give us a green light to initiate our pre-commercial strategy."
Individuals who present with clinical symptoms and evidence of non-specific neurological disease undergo a battery of tests in a diagnostic process that can take months or even years to complete. The diagnostic standard of care for MS includes CSF analysis using the OCB test alongside a comprehensive set of clinical tests to rule-out other neurological diseases. Unfortunately, the OCB test yields a high rate of false positive results, which can unnecessarily expose patients who do not have MS to chronic and expensive therapy that, in some cases, actually exacerbates their underlying disease. Alternatively, false negatives can delay the proper treatment of those patients who do have MS, possibly accelerating the development of permanent physical disability.
MSPrecise utilizes next-generation sequencing to measure DNA mutations found in rearranged immunoglobulin genes in immune cells initially isolated from cerebrospinal fluid. MSPrecise would augment the current standard of care for the diagnosis of MS by providing a more accurate measurement of a patient's immune response to a challenge within the CNS. This novel method of measuring changes in adaptive human immunity may also be able to discern individuals whose disease is more progressive and requires more aggressive treatment.
Source: The Sacramento Bee Copyright © The Sacramento Bee 2014 (27/01/13)
Researchers assess familial risks for MS using population registers, health care registries(22/01/14)
Even though multiple sclerosis is largely caused by genetic factors, the risk of patients' relatives developing the disease is lower than previously assumed. This is the conclusion of a new population registry-based study, published in the scientific journal Brain.
In the present study from Karolinska Institutet, researchers have assessed the familial risks for multiple sclerosis (MS) by using population registers and health care registries. This way, the researchers were able to include in their study almost everyone diagnosed with the disease in Sweden. Slightly over 28,000 individuals diagnosed with MS from 1968 onwards were identified. By using the Swedish Multi-generation registry, both biological and adopted relatives were identified and the researchers could assess the risks for the different groups.
This is the first study for MS in which the familial risks have been analysed using matched controls. By including randomly selected controls and their relatives, the researchers could also assess the risk for relatives of MS patients developing the disease compared to the risk for the population in general.
The estimated risks in this study turned out lower than the previously reported high risks. The risk for a sibling to a person with multiple sclerosis for developing disease was seven times higher compared to the general population, while the risk for a child of an MS patient was five times higher. The study found no increase in risk for grandchildren and nieces/nephews.
"The population registers in Sweden are reliable tools for finding relatives to MS patients and their possible MS diagnosis, instead of relying on the patients' memories. Our study is a good example of how one can quickly achieve more reliable results than the previous studies that were based on patient groups collected in hospitals throughout decades," says Helga Westerlind, a doctoral student at the Department of Clinical Neuroscience and first author of the article.
The researchers have also used the Swedish twin register to identify twins with multiple sclerosis and investigate how genes, shared environment and individual risk factors contribute to the disease. The analysis confirmed previous results: MS seems to be primarily caused by genetic factors, and secondarily by individual risk factors. A shared environment does not appear to be of any significance.
The study was funded by the Swedish Research Council, Karolinska Institutet, Stockholm County Council, the Bibbi and Nils Jensen Foundation and the Swedish Research Council for Health, Working Life and Welfare.
Source: News-Medical.Net (22/01/14)
MS research appeal(22/01/14)
An Orcadian geneticist who is researching the causes of MS in the Northern Isles, is asking people in Orkney to help create a list of all the people with Orkney and Shetland ancestors who have had Multiple Sclerosis.
Dr Jim Wilson who works for the Centre for Population Health Services at the University of Edinburgh said it is important to work out the degree to which MS is genetic in Orkney and Shetland, through building family trees of as many people as possible who have or had MS and asks for people to get in touch with information about “friends, neighbours, relatives or ancestors who had, or have MS.”
Orkney and Shetland have the highest prevalence of MS in the world, and this research has been undertaken as part of the Shetland and Orkney Multiple Sclerosis Research Project, which was set up to support research to try to understand why Orkney and Shetland have such high MS figures.
He said: “Medical studies now routinely use tens of thousands of subjects, but when trying to understand MS in Orkney we are always limited by the comparatively small total number of individuals with the disease. Building family trees back into the past and including everyone who had MS in the last 40 years is one way to increase our power to understand the disease.”
Anyone wishing further information on this research or to contribute, can contact Emily Weiss by email at firstname.lastname@example.org or by writing to her at Emily Weiss, Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EB8 9AG.
Source: The Orcadian © The Orcadian 2014 (22/01/14)
Norwegian researchers have mapped genetic variations associated with an increased risk of multiple sclerosis (MS) and myasthenia gravis (MG), bringing science one step closer to understanding these serious autoimmune disorders.
The Norwegian researchers have taken part in an international cooperative effort to map 110 genetic variations that increase the risk of MS and MG. Most of these genetic variations have been mapped in recent years.
"Rapid advances have been made in this area of research," explains Hanne F. Harbo, professor at the University of Oslo and head of the clinical science group at Oslo University Hospital.
She has received funding under the Research Council of Norway's national initiative on neuroscientific research (NEVRONOR) to head Norwegian research projects on MS and MG. The projects have been carried out in close cooperation with an international network of researchers.
Serious neurological and muscular disorders
Autoimmune disorders result from reactions by the body's immune system which in turn attack and destroy healthy cells.
"Our understanding of the causes of these diseases remains limited, but we do know that the immune system plays a key role in the debilitating processes that occur. MS attacks the central nervous system, causing inflammatory processes that lead to a variety of neurological symptoms including paralysis, loss of sensory function, and problems with vision and bladder function. MG affects the transmission of signals between the peripheral motoric nerve cells and muscles, resulting in muscular fatigue in the patient," Dr Harbo explains.
Genetic and environmental factors linked
Approximately 8 000 Norwegian are afflicted with MS. MG is far less prevalent, with only around 500 Norwegians affected.
One element preventing a better understanding of these disorders is that they are caused by a mix of genetic and environmental factors. They arise due to the unfortunate combination of genes that are associated with the disorders along with common factors occurring in the environment.
Viral infections - especially the Epstein-Barr virus – along with low levels of vitamin D in the blood and smoking are presumed to be moderate risk factors contributing to MS.
Finding new risk genes using genetic testing
Participating in large international research projects, Dr Harbo and colleagues have helped to identify a number of new risk genes for MS and MG. This has contributed significantly to a breakthrough in the genetics of MS.
The most important finding was that over 110 common risk variants show some sort of link to the risk of developing MS.
"We know that most of these risk variants on their own play little role in the development of MS. But mapping the collection of genes associated with MS represents an important advance in efforts to identify the key mechanisms behind its development," Dr Harbo says.
"Once we gain more insight into the mechanisms behind this disorder, it will be easier to shut down the pathways that trigger the disorder in cells," she concludes.
Common among the population
Approximately 150 of 100 000 inhabitants in Norway have MS, with the disorder afflicting more women than men and typically affecting young adults. The risk variant mostly highly associated with MS (HLA-DRB1*1501) triples the risk of developing the disorder.
"We know that the risk variant HLA-DRB1*1501 is common among the population and that its occurrence differs significantly among those who have MS and those who do not," Dr Harbo explains.
The Norwegian study of myasthenia gravis covers 370 MG patients and 650 healthy control subjects. The risk variant HLA-B*08 showed the highest risk for developing MG among young persons while HLA-DRB1*1501 posed the greatest risk among the elderly.
Genetic analyses solely as a research method
Genetic testing is not currently part of the clinical treatment of patients with MS or MG, and is only used as a research method for uncovering causal mechanisms. "Risk gene studies have provided new knowledge that is important to those working in the field. We will now move on to studying molecular mechanisms and how risk genes affect the clinical expression of the disorder," Dr Harbo explains.
The researchers have also examined environmental factors behind the incidence of MS and MG. Certain factors such as smoking appear to increase the risk of developing these disorders.
Targeting better treatment
There is no existing treatment to completely cure MS or MG, but new medications are constantly emerging that reduce inflammation and the role it plays in the disorder. "We hope to use our research findings to improve the knowledge base for developing more effective methods of treatment," Professor Harbo concludes.
Source: Medical Xpress © Medical Xpress 2011-2014 (10/01/14)
HERV-W polymorphism in chromosome X is associated with MS risk and with differential expression of MSRV(10/01/13)
Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis.
MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested.
Results: MSRV transcription levels were higher in MS patients than in controls (U-Mann-Whitney; p = 0.004).
Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A).
After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [chi2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann-Whitney; p = 0.039) or TT patients (U-Mann-Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann-Whitney; p = 0.003).
Conclusions: Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS.
Author: Marta GarcÃa-MontojoBelÃ©n de la HeraJezabel VaradÃ©Ana de la EncarnaciÃ³nIris CamachoMarÃa DomÃnguez-MozoAna Arias-LealÃ?ngel GarcÃa-MartÃnezIgnacio CasanovaGuillermo IzquierdoMiguel LucasMaria FedetzAntonio AlcinaRafael ArroyoFuencisla Mate
Source: 7thSpace Interactive © 2014 7thSpace Interactive (10/01/13)
The diseases have more than the immune system in common, sharing a genetic risk factor and connection to the Epstein Barr Virus.
Scientists at the Institute of Cancer Research (ICR) in London have discovered a genetic link between Hodgkin's lymphoma and multiple sclerosis (MS), suggesting that there may be a shared mechanism of action the triggers the two diseases.
Analyzing the genes of more than 12,000 people, the researchers found two new gene variants that increase the risk of developing Hodgkin's lymphoma significantly.
According to the study, “One of these variants is linked to a gene known as EOMES that helps develop cell-mediated immunity, and is also a known risk factor for MS. This might explain why cases of Hodgkin's lymphoma and MS are found to cluster together in families.”
What Is Hodgkin's Lymphoma?
Hodgkin's lymphoma is a cancer that starts in the white blood cells, or lymphocytes, found in the lymphatic system, which is part of the body’s immune system. Lymph nodes, lymph fluid, and lymph vessels, which transport the fluid throughout the body, all make up the lymphatic system.
Because this system runs throughout the body, Hodgkin's lymphoma can start nearly anywhere. According to the American Cancer Society (ACS), the major sites are the lymph nodes, spleen, thymus, bone marrow, and digestive tract.
Lymphocytes are also thought to play an important role in MS. Normally, lymphocytes defend the body against foreign invaders like viruses and bacteria. In MS, the lymphocytes are misdirected and attack the protective covering of the nerves in the brain and spinal cord.
In a study conducted in Denmark and published in 2004, researchers followed 11,790 patients with multiple sclerosis and 19,599 of their first-degree relatives and monitored them for the development of Hodgkin's lymphoma.
They concluded that “the observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin's lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.” The discovery of a genetic connection between Hodgkin's lymphoma and MS is exciting progress toward understanding both, suggesting the possibility of a mutual trigger.
EBV: A Possible Culprit?
If finding an MS trigger were a “whodunit,” the Epstein Barr virus (EBV), responsible for mononucleosis, would look like a handsome suspect. It is one of the known risk factors for developing Hodgkin's lymphoma and is commonly found in people with MS. EBV and MS appear to relapse together in those who have both.
“Epstein Barr virus is the virus that causes glandular fever (mononucleosis),” explains Cancer Research U.K. on their website. “People who have had glandular fever have an increased risk of Hodgkin's lymphoma afterwards. A study published in December 2011 estimated that almost half of the cases of Hodgkin's lymphoma in the U.K. are related to EBV infection.”
Not all people with Hodgkin's lymphoma or MS have been exposed to EBV, however, suggesting that if the virus is a trigger for either, it’s certainly not the only factor.
Researchers are working on the first human trials for a vaccine to fight EBV. Further research is needed to explore the connection between Hodgkin's lymphoma and MS.
The fact that both involve the immune system, share a genetic risk factor, and seem to cluster in families suggests that we are getting closer to solving the mysteries surrounding both diseases and are perhaps one step closer to a cure.
Source: Healthline Copyright © 2005 - 2013 Healthline Networks, Inc (07/11/13)
A major milestone has been reached on the path to finding a cure for multiple sclerosis (MS), researchers say.
A group of international scientists, including an Australian contingent, has discovered 48 previously unknown genes that influence the risk of developing MS.
MS, which attacks a person’s central nervous system and can impact mobility, balance and sensation, affects 23,000 Australians.
The new discovery is a big step towards finding a cure and further treatment for the debilitating condition, says University of Sydney Associate Professor David Booth, who led the Australian and New Zealand component of the study.
“The exciting thing about this is we have doubled the number of genes that we now know are associated with MS,” he’s told Sydney media.
“What that means is every one of those new genes is potentially providing us with a new way to understand the disease and to come up with new therapies for the disease.”
Researchers say they believe the findings underline the central role the immune system plays in the development of MS.
The results also show an overlap with genes found to be linked to other auto-immune diseases, including inflammatory bowel disease and coeliac disease.
The team of scientists, working under the umbrella of the International Multiple Sclerosis Genetics Consortium, has its findings published in medical journal Nature Genetics today (Monday, September 30).
As part of the study, the largest investigation of MS genetics to date, DNA from blood samples from 80,000 people with and without the condition were examined, including 1800 from Australia and New Zealand.
Professor Booth says the “milestone” provided specific research targets.
“So going forward we will try and find out why all of these genes affect MS,” he says.
“And particularly finding which processes are tagged by groups of genes and that will give us specific information on immune processes that are not functioning as they should.”
As a result of the new findings, there are now 110 genetic variants linked to MS.
MS Research Australia’s CEO Matthew Miles says the work is a huge contribution to understanding MS.
Source: Cowra Community News © 2013 Cowra Community News (30/09/13)
The National Institutes of Health (NIH) awarded Benaroya Research Institute at Virginia Mason (BRI) a $1.9 million grant to find marks in the human genome which can explain why some white blood cells cause damage to the spinal cord and brain in multiple sclerosis (MS). This is the first study to look for molecular changes in the genome of specific immune cells responsible for the devastation caused by MS. The broad-based study will determine the function of these cells, how they are generated and how they can be regulated in system models of MS and in humans.
"We want to understand the factors that make these cells target the spinal cord and brain to cause disease," says Estelle Bettelli, PhD, BRI Assistant Member and co-principal investigator of the study. Dr. Bettelli and other scientists have identified different types of T cells which they believe are potent inducers of MS and other autoimmune diseases. She has also developed system models to study different forms of multiple sclerosis.
"With Dr. Bettelli's research advances and with the new technological innovations in genome research, we can look at specific marks present in the genome of these cells and understand how they are generated and how they can be controlled," says co-principal investigator Steven Ziegler, PhD, Director of the BRI Immunology Research Program. Dr. Ziegler has used whole genome studies to investigate these cell types in healthy individuals. "We can then see how the genomic marks affect the cells in model systems of MS and how they operate in humans cells with and without the disease. We can also see how these cells behave once the patient receives treatment and if various treatments make the cells act differently."
"It is important to know how and when these cells are formed in the body to determine how to inhibit their harmful function," says Dr. Bettelli. "It is becoming clear that MS is not a unique disease entity but can present itself in different clinical forms and variants. Several factors, including the cell types involved, are believed to dictate the clinical progression of MS. The understanding of how and which cell populations of the immune system participate in the autoimmune attack is very important for determining current treatments and designing new therapeutics tailored to the different forms of MS. We hope to find ways to significantly inhibit these dangerous cells with new targeted medicines with fewer side effects.
"This work highlights a key mechanism for understanding and modifying the immune cells that cause autoimmune diseases like MS," says BRI Director Gerald Nepom, MD, PhD. "It is an exciting example of the power of merging new genomic technologies with state-of-the-art immunology research to address a major clinical need."
Other scientists collaborating in this effort are Jane Buckner, MD, BRI Associate Director, Damien Chaussabel, PhD, BRI Director of Systems Immunology, Mariko Kita, MD, BRI Affiliate Investigator and Director of the Virginia Mason Multiple Sclerosis Center, and John Stamatoyannopoulos, MD, Associate Professor of Genome Sciences and Medicine, University of Washington.
Multiple sclerosis is an autoimmune disease in which the body's immune system mistakenly attacks myelin, the fatty substance that surrounds and protects the nerve fibers in the central nervous system. When the myelin is damaged the nerve impulses are not transmitted as quickly or efficiently, resulting in symptoms such as numbness in the limbs, fatigue, dizziness, paralysis and/or loss of vision. Symptoms of MS will often improve and relapse with time and vary from one person to another. In progressive forms of multiple sclerosis, they gradually worsen.
MS affects approximately 400,000 Americans but is much more common in the Northwest. Some likely factors that contribute to this may be vitamin D deficiency, genetic predisposition and environmental triggers. Other factors are still unknown.
Source: EurekaAlert! Copyright ©2013 by AAAS (04/09/13)
MicroRNA are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed genome-wide expression analyses of mRNA and microRNA in T-cells from MS patients and controls.
Methods: Heparin-anticoagulated peripheral blood was collected from MS-patients and healthy controls followed by isolation of T-cells.
MicroRNA and RNA from T-cells was prepared and hybridized to Affymetrix miR 2.0 array and Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA), respectively. Verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).
Results: We identified 2,452 differentially expressed genes and 21 differentially expressed microRNA between MS patients and controls.
By Kolmogorov-Smirnov test, 20 of 21 differentially expressed microRNA were shown to affect the expression of their target genes, many of which were involved in the immune system. Tumor necrosis factor ligand superfamily member 14 (TNFSF14) was a microRNA target gene significantly decreased in MS.
The differential expression of mir-494, mir-197 and the predicted microRNA target gene TNFSF14 was verified by real-time PCR and ELISA.
Conclusion: These findings indicate that microRNA may be important regulatory molecules in T-cells in MS.
Author: Margareta JernÃ¥sClas MalmestrÃ¶mMarkus AxelssonIntawat NookaewHans WadenvikJan LyckeBob Olsson
Credits/Source: BMC Immunology 2013, 14:32
Source: 7thSpace Interactive © 2013 7thSpace Interactive (30/07/13)
A Western Australia-cohort of patients has been used to study the risk modifying role of specific genes suspected to contribute to one’s predisposition to multiple sclerosis (MS).
MS is the most common cause of neurological disabilities in young adults with an estimated 25,000 cases nationwide and a higher prevalence among women than men in most Western countries.
The Australian Neuro-muscular Research Institute’s Allan Kermode says this candidate gene selection study is validation research based on previously identified gene-disease associations.
“It needs to be interpreted in the context of other studies done,” Dr Kermode says.
Genome-wide association studies may have generated unforeseeable genetic associations but, “their weakness is that they use large groups of patients from diverse geographical and ethnic backgrounds—such patients can contaminate the group”.
Dr Kermode says the confirmation of individual gene variation effects on MS development in a highly categorised MS cohort of Anglo-Celtic origin—like the WA cohort, is valuable.
The study also provides evidence for interactive influences of gene combinations not studied before, some of which are described as protective.
“It could well be that certain genes are risk factors in some populations but not others,” says Dr Kermode.
“Lots of [immune regulatory] genes associated with MS are common and many people have them, but most of us do not get MS.
“The Human Leukocyte Antigen (HLA)-gene association remains the strongest association with MS risk,” and relates to the general understanding that autoimmunity underpins disease progression in this disorder.
But the idea that non-HLA genes contribute in parallel is well established now, supporting Dr Kermode’s interest in interactive effects of non-HLA with HLA-genes on MS risk.
He took a subset of the WA MS patients, who were selected for being carriers of the best known HLA-DRB1 risk gene in an Anglo-Celtic population, and studied its interaction with 10 non-HLA genes showing 16 sequence variations in MS patients and controls.
Dr Kermode says it also makes sense to consider interactions of environment stimuli and infections with HLA-genes, defining our immunity.
But their contribution to MS risk is dependent on one’s genotype, explaining why some do and others don’t develop MS.
He has started using the MS database to further investigate whether MS risk may be affected by vitamin D, as an immune modulator, or Epstein-Barr virus infections, which are 100 per cent prevalent in MS patients.
The inclusion of gene-environment interactions is hoped to improve stratification of MS patients and, in turn, the risk assessment of developing MS.
Notes: The Australian Neuromuscular Disease Research Institute (ANRI) is affiliated with the University of Western Australia and Murdoch University.
Source: Science Network Western Australia (15/07/13)
A UC San Francisco-led research team has identified the likely genetic mechanism that causes some patients with multiple sclerosis (MS) to progress more quickly than others to a debilitating stage of the disease. This finding could lead to the development of a test to help physicians tailor treatments for MS patients.
Researchers found that the absence of the gene Tob1 in CD4+ T cells, a type of immune cell, was the key to early onset of more serious disease in an animal model of MS.
Senior author Sergio Baranzini, PhD, a UCSF associate professor of neurology, said the potential development of a test for the gene could predict the course of MS in individual patients.
The study, done in collaboration with UCSF neurology researchers Scott Zamvil, MD, and Jorge Oksenberg, PhD, was published on June 24 in the Journal of Experimental Medicine.
MS is an inflammatory disease in which the protective myelin sheathing that coats nerve fibers in the brain and spinal cord is damaged and ultimately stripped away – a process known as demyelination. During the highly variable course of the disease, a wide range of cognitive, debilitating and painful neurological symptoms can result.
In previously published work, Baranzini and his research team found that patients at an early stage of MS, known as clinically isolated syndrome, who expressed low amounts of Tob1 were more likely to exhibit further signs of disease activity – a condition known as relapsing-remitting multiple sclerosis – earlier than those who expressed normal levels of the gene.
The current study, according to Baranzini, had two goals: to recapitulate in an animal model what the researchers had observed in humans, and uncover the potential mechanism by which it occurs.
The authors were successful on both counts. They found that when an MS-like disease was induced in mice genetically engineered to be deficient in Tob1, the mice had significantly earlier onset compared with wild-type mice, and developed a more aggressive form of the disease.
Subsequent experiments revealed the probable cause: the absence of Tob1 in just CD4+ T cells. The scientists demonstrated this by transferring T cells lacking the Tob1 gene into mice that had no immune systems but had normal Tob1 in all other cells. They found that the mice developed earlier and more severe disease than mice that had normal Tob1 expression in all cells including CD4+.
“This shows that Tob1 only needs to be absent in this one type of immune cell in order to reproduce our initial observations in mice lacking Tob1 in all of their cells,” said Baranzini.
Personalized Treatments for MS Patients
The researchers also found the likely mechanism of disease progression in the Tob1-deficient mice: higher levels of Th1 and Th17 cells, which cause an inflammatory response against myelin, and lower levels of Treg cells, which normally regulate inflammatory responses. The inflammation results in demyelination.
The research is significant for humans, said Baranzini, because the presence or absence of Tob1 in CD4+ cells could eventually serve as a prognostic biomarker that could help clinicians predict the course and severity of MS in individual patients. “This would be useful and important,” he said, “because physicians could decide to switch or modify therapies if they know whether the patient is likely to have an aggressive course of disease, or a more benign course.”
Ultimately, predicted Baranzini, “This may become an example of personalized medicine. When the patient comes to the clinic, we will be able to tailor the therapy based on what the tests tell us. We’re now laying the groundwork for this to happen.”
Co-authors of the study are Ulf Schulze-Topphoff, PhD, of UCSF; Simona Casazza, PhD, of UCSF at the time of the study; Michel Varrin-Doyer, PhD; and Kara Pekarek of UCSF; Raymond A. Sobel, MD, of Stanford University School of Medicine, and Stephen L. Hauser, MD, of UCSF.
The study was supported by funds from the National Institutes of Health (R01 grants NS26799, NS049477, AI073737, AI059709 and NS063008), the National Multiple Sclerosis Society, the Robert Tillman Family Fund, the Guthy-Jackson Charitable Foundation and the Maisin Foundation.
Source: UCSF © University Of California, San Francisco 2013 (25/06/13)
Multiple sclerosis, Crohn's disease, rheumatoid arthritis, and other inflammatory diseases may result from mutated genes that were once positive evolutionary adaptations, says new research.
The new study lends credence to the hygiene hypothesis, with evidence that gene variants that put people at risk for inflammatory diseases like multiple sclerosis were the target of natural selection over many generations in early human history.
The researchers, led by Dr. Philip De Jager of Brigham and Women's Hospital in Boston and Dr. Barbara Stranger of the University of Chicago, looked at existing genome-wide association studies and observed interactions among protein networks.
They found 21 places in the human genome that carry a "signature" for both natural selection and susceptibility to inflammatory disease.
The presence of gene signatures with those dual purposes suggests that in early human history, these gene variants became more prevalent in the human population because inflammatory responses helped protect us against viruses, bacteria and other pathogens.
In our modern world, however, most people no longer face exposure to the same environment and pathogens that our ancestors did. As a result, the genetic variants that originally protected us now make an autoimmune reaction more likely.
That interpretation of the results is consistent with the hygiene hypothesis, which posits that antiseptic modern environments actually contribute to the increasing prevalence of inflammatory diseases.
The hygiene hypothesis suggests that childhood exposure to germs in the environment can help strengthen the immune system against and protect children from developing allergies later on. Without early exposure to bacteria, children may become more vulnerable to inflammatory and autoimmune diseases.
Evidence suggests that these inflammatory diseases are much more common in the developed world, where antibiotics are used frequently enough to reduce children's exposure to microbes. As the world has become more hygienic, more people have been diagnosed with such conditions.
The study will be published in the April 4, 2013 issue of The American Journal of Human Genetics.
Source: Medical Daily © 2013 Medical Daily (25/03/13)
Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology(18/03/13)
Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical outcome.
Spinal cord pathology is common and contributes significantly to disability in the disease.
The influence of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown.
A post-mortem cohort of pathologically confirmed cases with multiple sclerosis (n = 108, 34 males) with fresh frozen material available for genetic analyses and fixed material for pathology was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15-positive (n = 21) and negative (n = 26) cases for detailed pathological analyses.
For each case, transverse sections from three spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons and inflammation. The influence of HLA-DRB1*15 on pathological outcome measures was evaluated.
Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure 15+: 23.7% versus 15−: 12.16%, P = 0.004), parenchymal (cervical, P < 0.01; thoracic, P < 0.05; lumbar, P < 0.01) and lesional inflammation (border, P = 0.001; periplaque white matter, P < 0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination through controlling the extent of parenchymal inflammation.
Meningeal inflammation correlated significantly with small fibre axonal loss in the lumbar spinal cord (r = −0.832, P = 0.003) only in HLA-DRB1*15-positive cases. HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord.
This study casts light on the role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked.
Source: Brain Copyright © 2013 Guarantors of Brain (18/03/13)
Summary: This research group tested whether genetic variation is associated with multiple sclerosis lesion topology by a genome-wide association study (GWAS). The researchers tested this hypothesis by analysing the distribution of multiple sclerosis lesions and used that measure as a trait in a GWAS.
They used voxel-level 3T magnetic resonance imaging T1 weighted scans to reconstruct the 3D topology of lesions in 284 subjects with multiple sclerosis and tested if this was a heritable phenotype. They computed the first ten principal components in order to focus on lesion distribution and carried out GWAS on each of these.
The researchers found 31 significant associations with component eight, which represents variation of lesion topology in the population. The majority can be linked to genes related to immune cell function and to myelin and neural growth.
The results show how quantitative traits derived from brain MRI can be used as dependent variables in a GWAS. In the future, the integration of imaging and genetic data sets is likely to become a mainstream tool for understanding the complex biological processes of MS.
Brain magnetic resonance imaging is widely used as a diagnostic and monitoring tool in multiple sclerosis and provides a non-invasive, sensitive and reproducible way to track the disease.
Topological characteristics relating to the distribution and shape of lesions are recognized as important neuroradiological markers in the diagnosis of multiple sclerosis, although these have been much less well characterized quantitatively than have traditional measures such as T(2) hyperintense or T(1) hypointense lesion volumes.
Here, we used voxel-level 3 T magnetic resonance imaging T(1)-weighted scans to reconstruct the 3D topology of lesions in 284 subjects with multiple sclerosis and tested whether this is a heritable phenotype. To this end, we extracted the genotypes from a published genome-wide association study on these same individuals and searched for genetic associations with lesion load, shape and topological distribution. Lesion probability maps were created to identify frequently affected areas and to assess the overall distribution of T(1) lesions in the subject population as a whole. We then developed an original algorithm to cluster adjacent lesional voxels (cluxels) in each subject and tested whether cluxel topology was significantly associated with any single-nucleotide polymorphism in our data set. To focus on patterns of lesion distribution, we computed the first 10 principal components.
Although principal component 1 correlated with lesion load, none of the remaining orthogonal components correlated with any other known variable. We then conducted genome-wide association studies on each of these and found 31 significant associations (false discovery rate <0.01) with principal component 8, which represents a mode of variation of lesion topology in the population.
The majority of the loci can be linked to genes related to immune cell function and to myelin and neural growth; some (SYK, MYT1L, TRAPPC9, SLITKR6 and RIC3) have been previously associated with the distribution of white matter lesions in multiple sclerosis.
Finally, we used a bioinformatics approach to identify a network of 48 interacting proteins showing genetic associations (P < 0.01) with cluxel topology in multiple sclerosis. This network also contains proteins expressed in immune cells and is enriched in molecules expressed in the central nervous system that contribute to neural development and regeneration. Our results show how quantitative traits derived from brain magnetic resonance images of patients with multiple sclerosis can be used as dependent variables in a genome-wide association study.
With the widespread availability of powerful computing and the availability of genotyped populations, integration of imaging and genetic data sets is likely to become a mainstream tool for understanding the complex biological processes of multiple sclerosis and other brain disorders.
Authors: Gourraud PA, Sdika M, Khankhanian P
Source: Brain. 2013 Feb 13. & Pubmed PMID: 23412934 (20/02/13)
Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis(20/02/13)
Summary: This study from the UK looked at gene-environment interactions in MS.
The researchers looked at the interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). They found that individuals exposed to both factors were at an increased risk of disease. Both DRB1-15 and IM status were independent predictors of disease, while there interaction term was not, but interaction on an additive scale was evident.
Based on this, if the additive model is appropriate, the DRB1-15 and IM may be part of the causal process leading to MS. This study demonstrates the importance of reporting gene-environment interactions on both a multiplicative and additive scale.
Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90).
In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%).
This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.
Authors: Disanto G, Hall C, Lucas R
Source: Mult Scler. 2013 Feb 14 & Pubmed PMID: 23413297 (20/02/13)
Nationwide surveys conducted in Japan over the past thirty years have revealed a four-fold increase in the estimated number of multiple sclerosis (MS) patients, a decrease in the age at onset, and successive increases in patients with conventional MS, which shows an involvement of multiple sites in the central nervous system, including the cerebrum and cerebellum. We aimed to clarify whether genetic and infectious backgrounds correlate to distinct disease phenotypes of MS in Japanese patients.
We analyzed HLA-DRB1 and -DPB1 alleles, and IgG antibodies specific for Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus, and Epstein-Barr virus nuclear antigen (EBNA) in 145 MS patients and 367 healthy controls (HCs). Frequencies of DRB1*0405 and DPB1*0301 were significantly higher, and DRB1*0901 and DPB1*0401 significantly lower, in MS patients as compared with HCs. MS patients with DRB1*0405 had a significantly earlier age of onset and lower Progression Index than patients without this allele. The proportion and absolute number of patients with DRB1*0405 successively increased with advancing year of birth. In MS patients without DRB1*0405, the frequency of the DRB1*1501 allele was significantly higher, while the DRB1*0901 allele was significantly lower, compared with HCs. Furthermore, DRB1*0405-negative MS patients were significantly more likely to be positive for EBNA antibodies compared with HCs.
Our study suggests that MS patients harboring DRB1*0405, a genetic risk factor for MS in the Japanese population, have a younger age at onset and a relatively benign disease course, while DRB1*0405-negative MS patients have features similar to Western-type MS in terms of association with Epstein-Barr virus infection and DRB1*1501. The recent increase of MS in young Japanese people may be caused, in part, by an increase in DRB1*0405-positive MS patients.
Satoshi Yoshimura, Noriko Isobe, Tomomi Yonekawa, Takuya Matsushita, Katsuhisa Masaki, Shinya Sato, Yuji Kawano, Ken Yamamoto, Jun-ichi Kira, the South Japan Multiple Sclerosis Genetics Consortium
Source: PLOS.org (14/11/2012)
Five scientists, including two from Simon Fraser University, have discovered that 30 per cent of our likelihood of developing Multiple Sclerosis (MS) can be explained by 475,806 genetic variants in our genome. Genome-wide Association Studies (GWAS) commonly screen these variants, looking for genetic links to diseases.
Corey Watson, a recent SFU doctoral graduate in biology, his thesis supervisor SFU biologist Felix Breden and three scientists in the United Kingdom have just had their findings published online in Scientific Reports. It's a sub-publication of the journal Nature.
An inflammatory disease of the central nervous system, MS is the most common neurological disorder among young adults. Canada has one of the highest MS rates in the world.
Watson and his colleagues recently helped quantify MS genetic susceptibility by taking a closer look at GWAS-identified variants in the major histocompatibility complex (MHC) region in 1,854 MS patients. The region has long been associated with MS susceptibility.
The MS patients' variants were compared to those of 5,164 controls, people without MS. They noted that eight percent of our 30-per-cent genetic susceptibility to MS is linked to small DNA variations on chromosome 6, which have also long been associated with MS susceptibility.
The MHC encodes proteins that facilitate communication between certain cells in the immune system. Outside of the MHC, a good majority of genetic susceptibility can't be nailed down because current studies don't allow for all variants in our genome to be captured.
"Much of the liability is unaccounted for because current research methods don't enable us to fully interrogate our genome in the context of risk for MS or other diseases," says Watson.
The researchers believe that one place to look for additional genetic causes of MS may be in genes that have variants that are rare in the population.
"The importance of rare gene variants in MS has been illustrated in two recent studies," notes Watson, now a postdoctoral researcher at the Mount Sinai School of Medicine in New York.
"But these variants, too, are generally poorly represented by genetic markers captured in GWAS, like the one our study was based on."
Simon Fraser University is Canada's top-ranked comprehensive university and one of the top 50 universities in the world under 50 years old. With campuses in Vancouver, Burnaby and Surrey, B.C., SFU engages actively with the community in its research and teaching, delivers almost 150 programs to more than 30,000 students, and has more than 120,000 alumni in 130 countries.
Source: Medical Xpress © Medical Xpress 2011-2012 (26/10/12)
New treatments for multiple sclerosis (MS) and other auto-immune diseases could flow from an important discovery made by scientists at NUI Maynooth.
They were trying to understand the role of a gene called Pellino3 and how it comes into play when a person develops a viral infection.
They found it acts as a “braking system” that helps to regulate the immune response during infection. Details of the work, led by Paul Moynagh, director of the Institute of Immunology at NUI Maynooth, are published today in the prestigious journal Nature Immunology.
The gene regulates production of proteins called interferons, explained Prof Moynagh. These are released by the body as soon as it detects an invading virus. As their name implies, they interfere with the virus’s ability to replicate and to invade nearby cells.
The release of these powerful proteins must be kept under check however, said Prof Moynagh. “If they are not tightly controlled the person can end up with auto-immune diseases.”
If too many interferons are released it can lead to inflammatory diseases such as lupus, while having too few available during infection can trigger diseases such as multiple sclerosis and support damage caused by other viruses such as hepatitis.
The 10 scientists in his group did intensive research into the role of Pellino3, using a mouse model, and have clarified its function in regulating the production of interferons. “Pellino3 seems to be a key molecule for switching interferons off,” he said.
Prof Moynagh, who is also the new head of the Department of Biology at Maynooth, won a Science Foundation Ireland principal investigator award in support of the research. The Health Research Board also backed the work via the PhD Scholars Programme in Immunology.
The team is now seeking ways to exploit the finding, which has “potential for the treatment of major auto-immune diseases”.
“The ultimate objective of our project is the development, production and commercialisation of pharmaceuticals which can help to combat immune-mediated diseases such as multiple sclerosis.”
The findings were also a clear example of the benefits of supporting basic research. This type of research “feeds the pipeline through which pharmaceutical development and disease treatment can occur”, said Prof Moynagh.
Source: IrishTimes.com © 2012 irishtimes.com (08/10/12)
Patients with multiple sclerosis (MS) can be differentiated according to their transcription profile, according to a study published in the Sept. 26 issue of Science Translational Medicine.
Linda Ottoboni, R.N., from the Brigham and Women's Hospital in Boston, and colleagues examined the structure of an MS patient population using a transcriptional profile generated from peripheral blood mononuclear cells.
Among 141 untreated patients, the researchers identified two subsets of MS patients (MSA and MSB). This structure was replicated in two additional groups of patients with MS, one treated with glatiramer acetate (94 patients) and the second treated with interferon-β (128 patients). Higher expression of molecules involved in lymphocyte signaling pathways was seen in subgroup MSA. In addition, patients in subgroup MSA were significantly more likely to experience a new inflammatory event while on treatment with glatiramer acetate or interferon-β.
"Overall, we report a transcriptional signature that distinguishes a subset of MS patients with more active disease," the authors write. "Stratifying MS subjects into meaningful subsets in this manner has potential for personalizing patient care and for enhancing our understanding of this disease."
Two authors disclosed financial ties to the pharmaceutical industry. Affymetrix Inc. produced the RNA data.
The multiple sclerosis (MS) patient population is highly heterogeneous in terms of disease course and treatment response. We used a transcriptional profile generated from peripheral blood mononuclear cells to define the structure of an MS patient population. Two subsets of MS subjects (MSA and MSB) were found among 141 untreated subjects.
We replicated this structure in two additional groups of MS subjects treated with one of the two first-line disease-modifying treatments in MS: glatiramer acetate (GA) (n = 94) and interferon-β (IFN-β) (n = 128). One of the two subsets of subjects (MSA) was distinguished by higher expression of molecules involved in lymphocyte signaling pathways.
Further, subjects in this MSA subset were more likely to have a new inflammatory event while on treatment with either GA or IFN-β (P = 0.0077). We thus report a transcriptional signature that differentiates subjects with MS into two classes with different levels of disease activity.
Source: Doctors Lounge Copyright © 2001-2012 Doctors Lounge & Science Copyright © 2012, American Association for the Advancement of Science (27/09/12)
Scientists have identified why a once-promising class of drugs do not help people with multiple sclerosis.
An Oxford University team say an genetic variant linked to MS means the drugs which work for patients with other autoimmune diseases will not work for them.
The team, writing in Nature, say the drugs can actually make symptoms worse.
Experts say the work shows how a person's genetic make-up could affect how they responded to treatment.
The drugs, called anti-TNFs, work for patients with rheumatoid arthritis and inflammatory bowel disease, but they have not done so for patients with MS and researchers were unsure why.
The Oxford University team looked at one particular genetic variant, found in a gene called TNFRSF1A, which has previously been associated with the risk of developing MS.
The normal, long version of the protein sits on the surface of cells and binds the TNF signalling molecule, which is important for a number of processes in the body.
But the team discovered the variant caused the production of an altered, shortened version which "mops up" TNF, preventing it from triggering signals - essentially the same thing that TNF blocking drugs do.
In the future, this could help ensure that people with MS are offered drug treatments that are most likely to work for them.
This explains why a study 10 years ago found the drugs make MS patients significantly worse and exacerbate the disease, the researchers suggest.
Professor Lars Fugger of the Nuffield Department of Clinical Neurosciences, who led the work, said: "The hope has been that analyses of the whole human genome would lead to findings that are clinically relevant.
"We show that this is possible. It's one of the first such examples, certainly in autoimmune disease."
He added: "Whilst the TNFRSF1A gene variant is linked to a modest risk of developing MS, the drug that mimics the effect of the variant has a considerably greater impact.
"The effects of genetic variants influencing disease risk or resistance can be amplified by drugs. This has often been completely overlooked, but will be critical for using genetic findings in a medical context."
Nick Rijke, director of policy and research at the MS Society, said: "There are many genes associated with MS, but we know little about the role they play or the influence they have on the condition.
"This important study has shown that some of your genes can play a part in deciding whether or not you respond to a treatment.
"In the future this could help ensure that people with MS are offered the drug treatments that are most likely to work for them."
Source: BBC News © British Broadcasting Corporation 2012 (09/07/12)