Background information about diabetes mellitus,alternative medicine for diabetes mellitus vs,type 2 diabetes and weight loss symptom 1177 - .


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Bacterial vaginosis, also known as BV, is a type of vaginal infection which is also the most common. This type of bacterial infection is often very uncomfortable and may present with a variety of different symptoms. Women who are experiencing foul smelling discharges and other symptoms should make an appointment with their doctors to get checked out.
Patients who present with only one or two BV like symptoms may have similar conditions such as yeast infections or Trichomoniasis.
Although the reasons for it are not quite yet fully understood, it appears that women who are sexually active and between the ages of fifteen and fifty are much more likely to contract the infection, though it is possible for virgins to come down with it. Mild antibiotics, either in pill or topical cream form, are generally prescribed by physicians to women suffering from BV. Unfortunately, although it isn’t yet understood why, it appears that girls who contract and are subsequently treated for bacterial vaginosis are extremely likely to contract the disease again. 2.1The Licensed Material may not be used in any final materials distributed inside of your company or any materials distributed outside of your company or to the public, including, but not limited to, advertising and marketing materials or in any online or other electronic distribution system (except that you may transmit comps digitally or electronically to your clients for their review) and may not be distributed, sublicensed or made available for use or distribution separately or individually and no rights may be granted to the Licensed Material. 2.2One copy of the Licensed Material may be made for backup purposes only but may only be used if the original Licensed Material becomes defective, destroyed or otherwise irretrievably lost. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. When our six-year-old daughter, Bisi, was hospitalized last summer after being diagnosed with type 1 diabetes, part of the torrent of information we learned is that some patients have a diabetes honeymoon period, where the pancreas starts working again—though not perfectly—after diagnosis.
Not all people enter a diabetes honeymoon period, but the majority do; in one study of 103 children under 12 with type 1 diabetes, 71 had a honeymoon. Bisi started off at 4 units of Lantus a day—that’s one shot of slow-acting insulin that lasts about 24 hours in the background.
We stayed at these numbers for maybe 6 weeks when suddenly, she started having unexplained lows. At her peak, right after diagnosis, Bisi was getting six insulin injections a day (plus all the blood tests). Still, we couldn’t help but look into alternative ways of pampering her resurgent (though still very weak) pancreas. Katie Bacon is a Boston-based writer and editor whose work has appeared in The Atlantic, The New York Times, The Boston Globe, and other publications. My five year old grandson was diagnosed at 2 years old with hemophilia, a bleeding disorder that does not allow his blood to clot. Katie, I love that you have learned so much and have done so much to try and extend the honeymoon. I’m so grateful for this blog as it helped me so much on the sleepless nights after returning from the hospital.
The Diabetes Media Foundation is a 501(c)(3) tax-exempt nonprofit media organization devoted to informing, educating, and generating community around living a healthy life with diabetes.
On the second Tuesday of every month, about 20 researchers from a dozen or so cities around the world get on the horn to participate in a conference call that has been happening regularly for nearly a decade. Incidence of multiple sclerosis in the United Kingdom : findings from a population-based cohort. Pathway and network-based analysis of genome-wide association studies in multiple sclerosis. Baranzini SE, Galwey NW, Wang J, Khankhanian P, Lindberg R, Pelletier D, Wu W, Uitdehaag B M, Kappos L, Consortium GMSA, et al.
Barcellos LF, Sawcer S, Ramsay PP, Baranzini SE, Thomson G, Briggs F, Cree BCA, Begovich AB, Villoslada P, Montalban X, et al. Gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone-induced demyelination.
Broadley S, Sawcer S, D'Alfonso S, Hensiek A, Coraddu F, Gray J, Roxburgh R, Clayton D, Buttinelli C, Quattrone A, et al. Everyone who signs up gets full access to our entire library, including our curated collections. Our Standard license allows you to use images for anything, except large print runs over 500,000+ or for merchandising.
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Although more commonly found in sexually active women, the illness is not defined as a sexually transmitted disease as it is not contagious or transmitted through intercourse.
The most common sign is the presence of a white and abnormal discharge in the affected person’s vagina. Physicians will swab the inside of her vagina and test the samples for its acidity and clue cells. All three illnesses are highly treatable and fairly common but receiving a definitive diagnosis is still helpful. These items help keep one another in check and prevent one type of organisms from multiplying so much that they lead to infections.
Recent studies have shown that women who use spermicides and condoms are slightly less likely to get the condition and that girls who are pregnant or already have a form of sexual transmitted disease are at a significantly higher risk. The most common regimen is one that is ingested or applied about every twelve hours for seven days.
The illness’s high recurrence rates seem to be related to both the particular antibiotics involved and the way human bodies respond to the original microorganisms. Except as specifically provided in this Agreement, the Licensed Material may not be shared or copied for example by including it in a disc library, image storage jukebox, network configuration or other similar arrangement. BackgroundTo enjoy a long and healthy life, everyone should make lifestyle choices that include a healthy diet, regular exercise, and maintaining normal weight. In other words, during prehistoric times, if a person couldn't move quickly and wasn't strong, that person died.
A 2007 review of existing studies found that moderate exercise, for as little as 5 minutes at a time, can help combat the nicotine withdrawal symptoms people experience when they try to stop smoking.
The United States Surgeon General recommends at least 30 minutes of moderate exercise, such as brisk walking, nearly every day.
The key to reaching and maintaining physical fitness is to find activities that are exciting, challenging, and satisfying. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions.
The theory, in layman’s terms, is that the hard-working pancreas has given up the ghost, but then revives a bit after getting the rest that outside insulin injections provide.
Francine Kaufman, the chief medical officer at Medtronic Diabetes who formerly ran the Center for Endocrinology, Diabetes and Metabolism at Children’s Hospital in Los Angeles, explained that whether a child has a honeymoon and how long it lasts depends on “a combination of virulence of the autodestructive process and when in the course of the disease the diagnosis is made.” In the hospital, Bisi’s doctors told us that a honeymoon period could last for a couple weeks, or months, or up to a year.
As Bisi’s diabetes nurse educator told me, “A honeymoon is a terrible name for it.” For the next while, we felt like we were constantly chasing Bisi’s lows—she’d have a series of lows, and we would reduce her dose. We already had her on a gluten-free diet, after my husband’s research turned up a study of a boy in Denmark who had been honeymooning for twenty months and counting after going gluten free.
Meanwhile, Bisi’s pancreas is sputtering along—I picture it as like the Vespa I once rode in Sicily—sometimes it’s speeding along faster than you’d expect, causing lows, other times it decides to conk out, causing highs. Richard Bernstein, the end of the honeymoon period is not  inevitable—though it’s very, very likely.
Our doctor suggested that taking vitamin D and omega threes could perhaps extend the honeymoon. It gave me hope and a vision of what I want to accomplish for my son’s type 1 diabetes.
The sun is just peeking over the Australian skyline when participants dial in from Melbourne and Sydney. If at any time you're unsatisfied with your experience with us, you can cancel your subscription. BV is caused by an imbalance of the body’s bacterial flora and features symptoms which are similar to that of a yeast infection. The results, combined with whether or not a fishy or tainted smell, should provide enough information for a proper diagnosis. It’s also a good idea to seek medical attention as soon as possible since, when left untreated, the illness can lead to serious complications. When one or more of the microorganisms responsible for bacterial vaginosis are allowed to multiply and flourish the condition is able to take hold. Recently, extended release capsules and other alternative treatments have been found to be particularly successful as well.  There is a natural alternative called Femanol that is known to be effective as well. Specialists estimate that roughly one out of every three girls will get BV during their lives. Once you license a royalty-free product, you may use it multiple times for multiple projects without paying additional fees.
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The combination of inactivity and eating the wrong foods is the second most common preventable cause of death in the United States (smoking is the first).
In addition, studies are reporting that even people at higher risk for heart disease may gain important protection from exercising. In the hospital, to be conservative, they started her off at one unit of Humalog for every seventy grams of carbohyrates she ate. Bisi had had no Humalog with her breakfast, and we’d given her a yogurt snack, which is normally enough to keep her blood sugar adequately high, even if she’s active. Yet as my understanding of diabetes and specifically the honeymoon has evolved, I’ve realized that staying on a bit of insulin is important—both so Bisi doesn’t get confused and think that she really doesn’t need shots, and to protect her pancreas from burning out sooner rather than it otherwise would. My husband also found a Canadian study of 42 people with T1D showing that “nearly half had an abnormal immune response to wheat proteins, while none of the 22 participants without diabetes had such a reaction. But from other parents I’ve talked to, the highs and lows of diabetes are much more difficult to manage once the honeymoon ends. In the eight months since she’s been honeymooning, we’ve thought the diabetes honeymoon was over several times—usually after holidays, when it is very difficult to limit her sugar intake because desserts are plentiful, and everyone around her is eating a lot of them. Bernstein is talking about—we just don’t feel like that would be sustainable for a young child.


We weren’t told anything about how the number of carbs Bisi eats could affect the length of her honeymoon.
Bernstein’s book and going as low carb as possible for a six year old with the goal of prolonging his honeymoon phase.
Their colleagues in Boston and other cities across the United States reach for their office phones during more reasonable work hours, while those in Norway, Finland, and Sweden might already be wearing pajamas. The Licensed Material may only be used in materials for personal, noncommercial use and test or sample use, including comps and layouts.
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Some researchers believe that with our current inactive lifestyle, these genes produce a number of bad effects, which can lead to many chronic illnesses.
Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. Over time, this ratio was adjusted downward, to a low point of 40 or 45 carbs per unit of insulin. If she’s getting a little bit of insulin, her pancreas won’t have to work so hard when she eats carbohydrates. When the researchers looked for a genetic cause of the immune cell overreaction, they found that it was linked to a gene associated with type 1 diabetes…. At that point, from my understanding, when the pancreas stops working for good and insulin needs are much higher, you are subject to higher highs, lower lows, and more dangerous swings between them. Bernstein was diagnosed with type 1 diabetes at age 12, and became a doctor in his late forties so he could better understand the disease that he felt was killing him through its complications. Her growing brain needs carbs, and she needs to have the freedom to eat more than just vegetables and protein. Bernstein (the Diabetes Solution and other books) suggests that  eating a low carb diet can extend the honeymoon indefinitely.
He weighs approx 25kg, has 160-200g of carbs daily and is on 8.5 units of insulatard and 1 unit novarapid daily. For the members of the International Multiple Sclerosis Genetics Consortium (IMSGC), the years of calls have held the group together, not just by keeping the far-flung collaborators informed of projects under way, but also by providing the means for would-be competitors to develop enough trust to share their hunches, their plans, and their data.  When the IMSGC formed, in 2002, the idea of competing labs pooling their resources—and of principal investigators forgoing primary authorship on research papers—was still novel. Meanwhile, after some night-time lows, they adjusted her Lantus downward from 4 to 3.5 to 3 units a day.
This is essentially the point made to me by Kaufman when I asked her if there are ways to extend the diabetes honeymoon.
According to the study’s authors, people with certain genes may be more likely to have an exaggerated immune reaction to foods like wheat, and this may spur other immune problems, like diabetes.” Bisi’s endocrinologist suggested we give her vitamin D, since there’s evidence that high vitamin D levels can extend the honeymoon.
Even though we sometimes do have to wake up to test Bisi in the middle of the night, those parents of children with diabetes whose honeymoon is over have to get up far more than we do—their kids are low, then high, then low again. He sharply improved his health by switching to a low-carb diet to normalize his blood sugars. Like Bisi, he is allowed to have an occasional treat of choice, but understands these are treats and not everyday fare.
Earlier this year more blood work revealed that I still have unusually high pancreatic function for someone with diabetes. I would like to see larger studies than the one you mentioned about the relationship between gluten and diabetes. My husband has found a couple of studies suggesting that going gluten free can extend the honeymoon. We’ve been bombarded with information since Feb but one thing I remember being told was that management was easier once the honeymoon period had passed. Any duplication or distribution of the information contained herein is strictly prohibited. There have been a couple of weekends—times when we’ve been very active, when Bisi hasn’t eaten many carbs—where she hasn’t needed insulin at all.
The important thing, she said, is to “stay in good control, and don’t stop insulin injections. If that is our future with Bisi, who can blame us for trying to delay it for as long as possible? So far I seem to be managing pretty well…but I am curious about whether or not I could prolong the honeymoon by switching to a mainly gluten-free diet.
The malady clearly clustered in families; 15% to 20% of patients have a relative with the disease, and having a twin with MS confers a 30% risk of developing the illness. On those weekends, what a huge relief it’s been to not worry about Bisi going low when she’s skiing or playing for hours at a water park—because she had no insulin in her system, there was no danger of her going low. An herbalist suggested that she take fenugreek, burdock, and nettles to strengthen her pancreatic function. Bernstein’s Diabetes Solution, he writes,  “Based upon my experience with the fair number of type 1 diabetics I’ve treated from diagnosis, I’m convinced that the diabetes  honeymoon period can be prolonged indefinitely. So for now, we’ll see if we can walk the fine line of protecting her remaining beta cells, while giving her enough of what she likes to eat. I wish you and your daughter the best of luck; it sounds like you are doing a great job figuring things out.
My mother’s instinct is to prolong it as much as possible and your post has given me a lot of food for thought. I’ve read Vitamin D supplementation is helpful to prolong the honeymoon, but nothing conclusive with strong results. They won’t cure type 1 diabetes, he told me, but he believes that herbs like these can extend the honeymoon. It’s hard not to have a tiny bit of hope that the diabetes honeymoon will continue and continue, but we also need to prepare ourselves that it won’t. The CDC did a study of him and determined that the only thing setting him apart from his counterparts is his diet. If we keep some if his cells alive who knows what treatments in the future become available to reverse or cure type 1.
The MHC family of genes, called the human leukocyte antigen (HLA) system in humans, encodes proteins on the cell surface that present antigens—typically, small chunks of foreign or a person’s own proteins—to T cells.
Not long after she was diagnosed, I asked her whether having diabetes was better or worse than she’d thought it would be when we first learned about her regimen. With the meticulous use of small doses of injected insulin and with the essential use of a very low carbohydrate diet, the remaining capacity of the pancreas, I believe, can be preserved.” The problem, Bernstein explains, is that by the time someone has been diagnosed with T1D, at least 80% of their beta cells, the ones that produce insulin, have been destroyed.
They theroize that the diet is causing his veins to be healthier and therefore harder to tear. Among other things, this process helps the immune system distinguish invaders from its own components. Researchers first correlated certain HLAs with MS in the early 1970s and, as genotyping technology evolved, traced the bulk of the disease-risk effect to specific alleles, or variants, of the genes, most significantly HLA DRB1*1501 (Barcellos et al., 1996).
What’s more, high blood sugar levels are thought to be toxic to these beta cells, so unless you are able to keep very tight control of your blood sugar levels, these cells will burn out one by one.
This locus accounted for a sizable chunk of the genetic, as opposed to the environmental, component of risk for the disease. Kaufman pointed out that there’s ongoing research to figure out how to “allow the beta cells present at diagnosis to survive.
Unlike disorders such as cystic fibrosis or Huntington disease, which stem from glitches in a single gene, MS arises from a combination of genetic and environmental factors. Each of the multiple genes involved exerts a small influence on whether someone develops the disease, as do a variety of environmental factors. She eat 50 carbs a meal, and we just started adding another bolus in the afternoon when needs, after school very hungry. Tracking this legion of modest effects required many more study subjects than scientists initially realized. A study published in August 2011, by far the biggest of its kind for MS, brought to 57 the number of spots on the human genome where variations were associated with increased risk of the disease. Since then, three more have been identified, and further follow-up work is poised to push the total number over 100 within the next year.
Geneticists are still developing basic techniques for analyzing such studies; figuring out which gene corresponds to a variant is far from straightforward, and identifying the function of any novel gene can consume an entire career. By the 1990s, researchers were beginning to realize the limitations of going solo, and small-scale cooperative efforts were beginning to emerge, for example among researchers in Nordic countries or across Australia and New Zealand. Most gene-mining projects had deployed a technique called linkage analysis, in which researchers use well-defined sequences of DNA as markers to track how risk for MS is inherited within individual families.
Markers close to the genes or sequences that stir up the biological trouble would be passed down with the miscreant DNA, pointing researchers to short stretches of the genome in which the culprits lie. Linkage studies work well to identify mutations that play a large role in a disease. But in cases of complex inheritance, when many alleles contribute to disease risk, related family members are likely to have different assortments, making the relevance of each one harder to demonstrate statistically and rendering linkage studies ineffective. A different approach was needed: association studies, which fish out disease-associated variants by comparing markers among large numbers of affected and unaffected individuals instead of comparing inheritance patterns within families. So-called genome-wide association studies (GWAS) scan hundreds of thousands of points along the genome and identify alleles that are more common in those who have the disease compared to those who do not. In the late 1990s, Compston, at Cambridge, decided to get groups across Europe to pool their samples and expertise and to take the first serious stab at conducting an association study for MS.
The collaborators called the effort GAMES (Genetic Analysis of Multiple Sclerosis in Europeans Consortium). A theoretical paper had suggested that a map of 6000 markers in 200 MS patients and 200 controls would provide sufficient statistical power (Barcellos et al., 1997). As knowledge about immunology exploded, showering the terrain with newly discovered molecules, he realized that he and his colleagues needed a scaffold for MS on which to hang these immune components. He reached out to genomicist Eric Lander, then also at Harvard, to learn about complex genetics and genome sequencing. By 2002, those founders of the IMSGC who had already been involved with genetics consortia dedicated to MS began to discuss how they could again work together; Hafler also began to chat with Stephen Hauser of the University of California, San Francisco, about the idea of a new international consortium for MS. At around this time, while at a conference in Copenhagen, Hafler and Compston continued those conversations with several colleagues including Haines and Margaret Pericak-Vance, now at the University of Miami in Florida. They envisioned an ambitious goal: discovering all of the common genetic risk variants in MS. A Boston venture capitalist named Martha Crowninshield, who has a long-standing interest in MS and has remained closely involved with the IMSGC’s work, helped them refine the proposal and contributed the first $1 million. She also hosted an event at which a handful of potential donors were invited to hear about the consortium’s plans from Hafler, Lander, and Joseph Martin, then the dean of Harvard Medical School.


We started working on this problem in the early 1980s, and now it’s 30 years later.’” The initial crew members knew they would have to replace guarded competition with trust, so one of their first steps was to create a charter—appropriated and amended from the International Inflammatory Bowel Disease Genetics Consortium—that addressed issues such as authorship, seniority, sample and data sharing, bringing in new members, and settling disputes.
This policy was meant to ensure that the boundaries between IMSGC projects and individual labs’ work were known to everyone in advance. The founding members also agreed that the collaboration would stay small until time had proven that it could work. First on the group’s agenda, then, was a linkage study to end all linkage studies—that is, a linkage study powerful enough to definitively determine whether the technique could identify genetic risk factors outside the MHC. The answer to the question, based on a study of 700 families, turned out to be a resounding “no” (Sawcer et al., 2005).
The analysis once again pointed to the HLA DRB1*1501 allele in the MHC, and it identified no other signals anywhere near as strong, despite being many orders of magnitude more sensitive than previous MS linkage studies.  Meanwhile, the technology that powers genetic research was on the verge of a revolution. In the 2000s, researchers were turning to single-nucleotide polymorphisms (SNPs)—single-base variations in the genome—which could serve as much denser, more accurate markers than those previously used.
Initiatives sparked by the Human Genome Project, such as the SNP Consortium and the International HapMap Project, were identifying tens of thousands of SNPs common enough to be found in 1% to 5% of the population.
This development meant that researchers could use a microchip that contained upward of 100,000 such SNPs to scan a person’s entire genome and assess which variants were more common in people with a specific disease.  With linkage a failure, the group was divided about how to proceed. Some members were eager to try GWAS in MS; however, the technique was costly and unproven, and others thought it more prudent to wait for the technology to mature. Researchers linked its overactivity to the disease in a 2001 report of 15 patients with relapsing-remitting MS (Ramanathan et al., 2001), but subsequent studies of the gene were inconclusive.
When IMSGC participants and others further investigated the gene, they found that the risk variant changes how it is spliced, which likely causes it to generate reduced amounts of the protein’s alpha chain in the membrane and increased amounts in the cytoplasm (Gregory et al., 2007).
Because this portion of the protein must lie in the membrane for the receptor to work properly, the location change curbs its ability to do its job.
Away from the membrane, it is no longer available to respond to a cytokine called IL-7, which normally helps certain lymphocytes survive and promotes development of B and T cells. Perhaps dampening T- and B-cell maturation could knock immune cell function off kilter and contribute to MS, researchers conjectured. Researchers took a long time to understand how many subjects were needed to render GWAS useful, Sawcer says, in large part because the number required depends on the relative number of SNPs and risk genes—and on how strongly the genes involved boost the likelihood of getting the disease. Taking these issues into consideration, investigators have now calculated that a minimum of 2000 cases and as many controls are needed to achieve statistical significance, Sawcer says—about twice as many individuals as were included in the 2007 study. Additional subjects would increase the study’s power even more. As other susceptibility loci—most of them with unknown roles in the body—began to trickle in through subsequent studies, the group began planning a GWAS with 10 times as many patients. Several consortium members estimate that the IMSGC now comprises about 9 out of every 10 researchers working on MS genetics worldwide. Candidates must bring something new to the group—almost always patient samples, although in some cases, expertise. Going through written approvals and waiting for materials to be aliquotted, checked, and shipped from a home laboratory could easily add 6 months to an experiment. In contrast, the consortium repositories are geared to prep large numbers of samples for action as quickly as possible.  That setup helped the consortium to get moving on its latest GWAS, a $5 million to $6 million effort that included 9772 patients and 17,376 controls. It was conducted as part of the Wellcome Trust Case Control Consortium, a massive study of genetic variation in common diseases. The resulting report, published in August 2011, scanned about 600,000 SNPs—covering approximately 80% of the genome—and brought the total number of confirmed risk variants for MS to 57 (IMSGC et al., 2011). Because these features are present from before birth, he says, “the genetics are telling us about the earliest events in MS—events we were never really able to capture before.” An initial analysis, in which researchers looked for associations between the risk genes and other aspects of the disease, such as its type and severity, suggested that these genes might play a role in whether a person gets the disease, but not in the disease’s course. If that’s the case, the genes might not prove to be good targets for new therapies, says Jan Hillert, a neurologist at the Karolinska Institute in Stockholm, Sweden, who started the Nordic MS genetics consortium in 1994 and joined the IMSGC about 4 years ago. The vast majority of genes identified in the study have immune functions, De Jager says, strongly supporting the latter explanation. Sergio Baranzini, an MS geneticist at the University of California, San Francisco, points out that tremendous overlap exists between genes that operate in different physiological processes, and that the so-called immune genes could also function in the nervous system.
Many of the genes with the strongest association to MS, including HLA DRB1*1501, appear to be regulated by vitamin D, says MS geneticist George Ebers of Oxford University in the U.K.
Because vitamin D levels strongly depend on sunlight, the observation fits with epidemiological studies showing that lack of sun exposure is an important risk factor for the disease.
A study published in December 2011, which identified three more variants in addition to the 57 found in the latest GWAS, also compared risk genes for MS with those for ulcerative colitis, diabetes, psoriasis, and other autoimmune diseases.
It found that a sizable minority of risk genes shared with celiac disease and other conditions have an opposite effect—protective rather than injurious—to that in MS (Patsopoulos et al., 2011). But researchers are slowly starting to tie the known MS risk genes to biological processes that could affect disease onset (see "Altered Immunity, Crippled Neurons").
Kilpatrick’s group is studying a family of proteins known as the TAM receptors, one of which—MERTK—is associated with MS. At least one plasma-borne TAM receptor ligand shows initial promise as a biomarker of disease, Kilpatrick said during a presentation at the November 2011 Society for Neuroscience meeting in Washington, D.C. Such studies are beginning to show how some genes might be involved in MS, but they so far provide only the barest hints of mechanism. Understanding the functions of genes uncovered by GWAS starts with mapping the precise location of the SNPs that identify a risk variant. Some SNPs lie in the protein-coding section of the gene, making it likely, researchers say, that the genetic spelling variations correspond to codon differences.
But the vast majority of SNPs reside in difficult-to-interpret areas, either in introns—stretches within a gene that can influence which versions of it are transcribed—or in even murkier regions between genes. Furthermore, a variant on one part of the genome can control a gene on a completely different chromosome.
Often, the matchup between SNP and gene is a best guess, made by choosing the closest known gene. Sometimes the gene can be identified by a process called fine-mapping, in which researchers use an increasing number of markers to home in on sequences in nearby regions, “but a lot of these areas just won’t break down with fine-mapping,” Kilpatrick says. His group identified one risk locus on chromosome 12 that could have been tied to any one of 17 genes. Researchers ascribed it to a gene called CYP27B1, which is involved in converting vitamin D to its active form, simply because that made the most sense, he says, but that is a so-called biased approach.
Progress might not be linear, however; some argue that it will come only when a critical mass of risk variants is identified. But with 50 or 100 SNPs associated with the disease, “we can start mapping to hopefully coherent pathways.” Uncovering missing heritabilityEach gene identified by the IMSGC represents a minuscule portion of the disease’s heritability, at least in the simplest analysis. Researchers use a measure called an odds ratio to describe the size of an effect; the greater than 1 it is, the greater the likelihood that the SNP or gene in question is associated with the disease. Researchers say that the 60 genes outside the MHC together explain only a small percentage of MS’s heritability, significantly less than that explained by the MHC. IMSGC scientists posit that even with small effect sizes, genes could reveal pathways that play a central role in the disease.
But, he adds, “if I was spending this amount of time and money on this and I came up with genes that explain [so little] of the risk, I’d be disappointed.” Part of the problem might lie in the assumptions underlying the interpretation of GWAS data.
Risk alleles are generally treated additively in statistical analyses, simply because this is the easiest way to model the enormous amounts of data that GWAS produce.
The method, however, does not incorporate the possibility that genes’ activities could combine in more complicated ways. In May 2011, Michael Demetriou, an immunologist at the University of California, Irvine, identified a connection between MS and disruption of a process called N-glycosylation, which attaches complex sugars to proteins and can modify their function (Mkhikian et al., 2011).
The IL2RA, IL7RA, and MGAT1 risk alleles—but not those associated with other genes—disrupt N-glycosylation and cause symptoms characteristic of MS in mice.
When the three are present together, however, MGAT1 negates the deleterious effects of the other two. Vitamin D delivers the same mitigating effect, revealing a complex interplay of genetic and environmental factors.
A paper published in January by Lander’s group at the Broad Institute in Cambridge, Massachusetts, suggests that this idea might be generally true for illnesses associated with relatively common gene variants, but identifying such interactions might require enormous studies of hundreds of thousands of patients (Zuk et al., 2012). So far, however, no clear method exists for systematically detecting how risk variants enhance or slash one another’s effects, he adds. Results to date suggest that common variants do appear to behave additively, De Jager says, “but the problem is that the studies are underpowered to detect” synergistic interactions that might be present. Gene interactions might be particularly relevant in specific subsets of patients, he says, but currently no meaningful approach parses out such groups. Hillert’s lab is working on a database that will tie information about individuals’ disease course and relevant environmental factors—whether they smoked or were infected with Epstein-Barr virus (EBV), for example—to their genotype in order to begin systematically searching for such interactions (see "Viral Villain"). Researchers within and outside the IMSGC propose several other possibilities for where the missing heritability might lie. First, with GWAS to date covering only about 80% of the genome, additional common risk variants might lie in areas with poor SNP coverage. Additionally, Baranzini notes, risk alleles might be distributed along key pathways that are misregulated in the disease. For example, a particular SNP associated with the disease might be found in, say, 20% of the population. But another SNP, present in another 20% of the population, might participate in the same physiological process as the first one. Uniting all of these small effects under the umbrella of a single pathway might flush out more of the missing heritability. Another avenue of exploration is rare variants that occur sporadically in certain families but are uncommon in MS patients in general. Such variants can’t easily be found with GWAS; rather, their identification requires whole-genome sequencing or at least sequencing of the coding region of the genome and comparing the results among affected and unaffected family members. Techniques to carry out such experiments are becoming available, and Baranzini and his colleagues have sequenced DNA from 12 individuals in one family: siblings, cousins, and an aunt, of whom six have the disease and six do not.
A handful of reports have suggested that the risk of developing MS differs depending on whether individuals inherit a particular allele from their father or their mother.
Such a pattern would arise if the chromosomal regions harboring these genes are “imprinted,” carrying epigenetic marks that turn genes on and off.            Meanwhile, IMSGC researchers are focusing on the identified risk alleles to determine whether they can somehow be used to predict the chances that an individual will get MS—not in the general population, but in people who have a close relative with it or who have experienced an isolated neurological episode or have MS-like lesions. De Jager’s group is developing an algorithm that uses genetic and environmental information to stratify such people based on their risk. The researchers are now conducting a study to determine which, if any, of these factors correlate with asymptomatic disease, as captured by MRI. With the identification of the common risk variants for the disease close to its logical conclusion, researchers are now well positioned to transform current knowledge into a springboard for the next stage of research. Despite the complexity and the caveats, IMSGC researchers say, the investment so far has been well worth it. How much do they uncover novel disease mechanisms?What can genes that are associated with other autoimmune disorders contribute to researchers’ understanding of MS?Are any genetic markers associated with subpopulations of patients (according to disease type or lifestyle factors, for instance) or disease factors such as viral status or response to specific therapies?



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