Health scientists at the University of Leicester and University of Nottingham have heralded the discovery of a gene associated with lung fibrosis as ‘a potential new avenue of treatment for further research into this terrible disease.’
Idiopathic Pulmonary Fibrosis (IPF) is a debilitating lung disease, affecting ~6,000 new people each year, where scarring (fibrosis) of the lungs makes it difficult to breathe.
IPF, on average, results in death 3 years after diagnosis. There is no cure for IPF, and currently available drugs can only slow the disease down, and do not stop, or reverse, it. Furthermore, some patients may suffer unpleasant side-effects. A better understanding of the disease is needed to develop even more effective treatments.
Researchers Professor Louise Wain from the University of Leicester and Professor Gisli Jenkins from the University of Nottingham were lead authors of the study.  They analysed the DNA from over 2700 people with IPF and 8500 people without IPF from around the world and found that people with IPF are more likely to have changes in a gene called AKAP13.
The researchers were also able to show that these DNA changes affect how much AKAP13 protein is produced by the gene in the lungs.  Researchers know from other studies, that AKAP13 is part of a biological pathway that promotes fibrosis (or scarring) and importantly that this biological pathway can be targeted with drugs. Taken together, the findings suggest targeting this pathway with drugs in people with IPF might lead to new treatments. To confirm this, the research team now need to undertake more detailed studies into the role of AKAP13 in people with IPF.
The work was led by researchers at Leicester and Nottingham and brought together collaborators from around the world to form the largest combined analysis of people with IPF undertaken to date.

Leicester University
www2.le.ac.uk/offices/press/press-releases/2017/october/leicester-and-nottingham-scientists-discover-new-gene-associated-with-debilitating-lung-disease

Notch is one of the most frequently mutated genes in chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults in the United States. It is also often mutated in other common B cell tumours, such as mantle cell lymphoma. However, the role of Notch in these cancers has been uncertain. Now, a collaborative effort between investigators at the Perelman School of Medicine at the University of Pennsylvania and the Harvard Medical School provides new insights into how Notch drives the growth of B-cell cancers.
The researchers found that in B cell tumours, mutated overactive versions of the Notch protein directly drive the expression of the Myc gene and many other genes that participate in B cell signalling pathways. Myc is a critical gene in governing cell proliferation and survival, activities that it carries out by regulating the expression of other genes involved in cell metabolism.
B cell signalling pathways are the current targets of several therapies used to treat B cell malignancies such as CLL. “An important translational implication of this research is that we hope that by combining Notch inhibitors with drugs that target B-cell signalling we can better treat these B-cell cancers,” said senior author Warren Pear, MD, PhD, a professor of Pathology and Laboratory Medicine at Penn Medicine. “Although this is true of many transcription factors, it has been difficult to develop therapeutics that directly target the Myc protein, an alternative approach may be to target the proteins that regulate Myc expression.” Notably, multiple Notch inhibitors are in various stages of clinical development as potential cancer therapies.
The mechanism used by Notch to regulate Myc in B cells is distinct from the mechanism used in other cell types, such as T cells, where Notch also regulates Myc. The team found that Notch uses different regulatory switches in the genome, called enhancers, in different cell types. This raises the issue of why evolution would select for this complexity. One reason may be that Myc needs to be under very tight control in each cell. For example, in the mouse model of Notch-induced T-cell leukemia, the Penn group previously found that the difference between inducing a T cell tumor or not is a doubling of Myc transcription by Notch. As Notch appears to use cell type-specific machinery to regulate Myc, it may be possible to target the Notch-Myc signaling path in a way that does not disrupt this path in other cell types.
Another surprising finding was the direct link between Notch and genes involved in other B cell signalling pathways. For example, Notch activates genes involved in B cell receptor signalling, which is an established drug target in these B cell cancers. The challenge now will be to understand what this might mean for treatment of patients with Notch-activated B-cell leukemias and lymphomas. The team plans to test the synergy between Notch and B-cell signaling inhibitors. If they find a relationship, the next step would be to stimulate interest in a clinical trial.

Penn Medicine
www.pennmedicine.org/news/news-releases/2017/october/penn-study-links-mutations-in-notch-gene-to-role-in-b-cell-cancers

A new five-year study of nearly 1,600 patients finds that genetic testing can help determine the safest dose of the blood thinner warfarin, with fewer side effects, in patients undergoing joint replacement surgery.
Considering a patient’s genetic makeup when prescribing warfarin—a blood thinner commonly prescribed to prevent life-threatening blood clots—can mean fewer adverse side effects like haemorrhage, researchers found.
Warfarin is a commonly prescribed, very effective anticlotting medicine — but it’s often associated with adverse complications and each patient requires a different dosage to achieve the desired treatment effect.
That unique dosing is based in part on an individual’s genetics, and great interest exists in understanding whether an individual’s genetics can guide how to best prescribe warfarin to reach the optimal therapeutic range.
Now, researchers from Intermountain Medical Center, along with four other research centers, including Washington University School of Medicine in St. Louis, which led the national study, have shown that outcomes greatly improve for older patients who undergo elective hip or knee replacement when the dose of warfarin is based on how a patient’s liver metabolizes the blood thinner, which can be discovered using a blood test.
Researchers say study findings from the GIFT study (Genetics Informatics Trial of Warfarin to Prevent Deep Venous Thrombosis) are significant. Compared to patients who received a standard dose, patients who received genetically-dosed warfarin had a 27 percent reduction in complications.
Specifically, their major bleeding was reduced by 75 percent, the incidence of excessive international normalized ratios was reduced by about 30 percent, and blood clots occurred 15 percent less often. No patients died during the study.
The findings from the GIFT study are published and could be used immediately. The Food and Drug Administration has since 2007 included language in its warfarin packaging that encourages the use of genetic guidance, if it’s available.
“Differences can be identified by looking at a patient’s genetic makeup, and specifically at the genes that are responsible for the liver’s metabolism of the drug,” said Scott Woller, MD, co-director of the Thrombosis Program at Intermountain Medical Center and principal investigator for Intermountain Healthcare.

Intermountain Healthcare
intermountainhealthcare.org/news/2017/10/genetic-testing-can-help-determine-safest-dose-of-warfarin-for-joint-surgery-patients/

What role do genes play in egg, milk, and nut allergies? A study, led by the Max Delbrück Center for Molecular Medicine (MDC) and Charité – Universitätsmedizin Berlin, has found five genetic risk loci that point to the importance of skin and mucous membrane barriers and the immune system in the development of food allergies.
An estimated five to eight percent of all children suffer from food allergies. They usually appear in the first years of life and manifest themselves in the form of itchy rashes and facial swellings, which occur shortly after food ingestion. Food allergies can, however, also cause severe allergic reactions involving breathing difficulties, vomiting, or diarrhea, and are the most frequent triggers of anaphylaxis in children. Anaphylaxis is the most extreme form of an immediate allergic reaction and can be life threatening.
In Germany, chicken eggs, cow’s milk, and peanuts are the most common causes of allergic food reactions in children. Unlike allergies to cow’s milk and chicken eggs, which often disappear after a few years, children generally do not outgrow allergies to peanuts. Peanut allergy sufferers must follow a strict diet for their entire lives and carry emergency medication with them at all times.
The causes of food allergies involve a complex interplay of genetics and environment. “Studies of twins suggest that about 80 percent of the risk for food allergies is heritable, but little is known so far about these genetic risk factors,” says Prof. Young-Ae Lee, a researcher at the MDC and head of the Charité‘s outpatient pediatric allergy clinic.
A genome-wide association study examined some 1,500 children in Germany and the United States who suffer from food allergies. The research looked at more than five million genetic variations, called single nucleotide polymorphisms or SNPs (pronounced “snips”), in each participant in the study and compared the frequency of these SNPs with that of the control subjects. The study involved researchers from Berlin, Frankfurt, Greifswald, Hanover, Wangen, and Chicago. It is remarkable not only for its size but also for its reliable diagnostic methodology.
Unlike other studies, the researchers used an oral food challenge test to confirm the allergy diagnosis. This is a complex procedure in which patients ingest small amounts of the suspected allergen in the hospital under emergency conditions to determine if they respond allergically to it. “We know from clinical practice that as many as 80 percent of presumed food allergies are not actually allergies. These food sensitivities are frequently due to food intolerance rather than an allergic response,” says Prof. Lee.
This study discovered a total of five genetic risk loci for food allergies. Four of them show a strong correlation with known loci for not only atopic dermatitis and asthma, but also for other chronic inflammatory diseases like Crohn’s disease and psoriasis as well as autoimmune disorders.

New risk locus associated with all children’s food allergies
The so-called SERPINB gene cluster on chromosome 18 was identified as a specific genetic risk locus for food allergies. It involves ten members of the serine protease inhibitor (serpin) superfamily. The genes in this cluster are expressed primarily in the skin and in the mucous membrane of the oesophagus. The researchers thus suspect that they play a major role in ensuring the integrity of the epithelial barrier function. Another important finding of the study is that four of the five identified risk loci are associated with all food allergies. The human leukocyte antigen (HLA) region, which is specific to peanut allergy cases, appears to be the only exception.
The study provides a basis for the development of better diagnostic tests for food allergies and for further investigation into their causative mechanisms and possible treatment strategies. Parents should not make decisions about avoiding specific foods on their own, but should instead seek out a specialist if their child appears to have a food allergy.
Max Delbrück Center for Molecular Medicine (MDC)
insights.mdc-berlin.de/en/2017/10/study-provides-clarity-genetic-causes-childrens-food-allergies/

While the microbiome has gained significant attention for its impact on digestive health in recent years, its effect on lung disease has largely remained unstudied.
Dr. Patricia Finn says this is a missed opportunity.
“The microbiome is the ecosystem of good and bad bacteria living in the body,” said Finn, the Earl M. Bane Professor of Medicine at the University of Illinois at Chicago. “Because the lungs continuously and automatically draw air, and any number of environmental agents, into the body, the composition and balance of microbes in the lungs may have a profound effect on many respiratory conditions.”
New research from Finn and her colleagues in the UIC College of Medicine suggests that the lung microbiome plays a significant role in asthma severity and response to treatment.
Asthma is a chronic disease in which lung airways become swollen and narrow, making it difficult for air to move in and out of lungs. Because people with asthma have inflamed airways, they experience a range of symptoms, including shortness of breath, coughing, wheezing and chest tightness.
In a group of clinically similar patients with asthma, researchers identified two asthma phenotypes by assessing the microbiome and airway inflammation. The patients were ages 18 to 30 with mild or moderate atopic asthma.
“This tells us the microbiome has relevance beyond the gut, and that it is a potential biomarker for asthma,” said Dr. David Perkins, professor of medicine and surgery at UIC, who jointly operates the lab with Finn.
These two phenotypes, called asthma phenotype one and two, or AP1 and AP2, are demarcated by the prevalence and dominance of different bacteria in the lung. When compared, patients in the two groups performed differently on pulmonary function tests.
AP1 was associated with less severe asthma; it showed decreased T helper cytokines and increased enterococcus bacteria, but normal pulmonary function tests. In contrast, AP2 was associated with increased pro-inflammatory cytokines, increased oral taxa and strep pneumonia bacteria, and decreased pulmonary function tests, or more severe asthma.
In both AP1 and AP2, the associations between the composition of the microbiome and specific inflammatory cytokines were decreased after treatment with an inhaled corticosteroid, a common asthma therapy. Researchers say this suggests that ICS may function by dampening responses to microbes.
“The data suggest that further study of the microbiome may help to develop more personalized treatment recommendations for patients with asthma,” said Finn, the senior author on the paper.
Finn says that asthma research has increasingly focused on the differences between seemingly similar patients, and that this study adds to the growing body of evidence that patients benefit from precision medicine approaches to common chronic diseases, such as asthma.
“If we can better understand how the individual’s lung microbiome affects asthma and identify likely microbial culprits, we may get to a point where we can predict and control asthma development and severity by shifting the microbiome early in life,” Finn said. “This could be as simple as diet, probiotics or medication.”
University of Illinois – Chicago
today.uic.edu/new-asthma-biomarkers-identified-from-lung-bacteria