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

Several patients with recurring glioblastoma, a deadly brain cancer, survived for more than a year in a clinical trial believed to be the first to use comprehensive DNA and RNA sequencing of a patient’s tumour to inform treatment for these patients in real-time. The study was led by the Translational Genomics Research Institute (TGen), UC San Francisco (UCSF) and the Ivy Foundation Early Phase Clinical Trials Consortium.
"To our knowledge, this is the first report of a prospective profiling study in recurrent glioblastoma to show patients with extended time to progression following treatment with genomics-informed therapy," said Dr. Sara Byron, Research Assistant Professor in TGen’s Integrated Cancer Genomics Division and the study’s lead author. "This is a primary example of the benefits of genomics-driven precision medicine being applied for patients with aggressive and refractory tumours."
Fifteen of 16 glioblastoma patients in the study conducted at UCSF received TGen’s genomics-informed treatment recommendations, in which the therapeutics suggested by a medical review panel (UCSF’s Molecular Tumor Board) were matched to each patient’s particular genetic code. Of those 15, seven patients were treated by their physicians using the genomic-based recommendations.
Key to this study was the fact that all genomic sequencing (the spelling out of the chemical DNA and RNA bases for more than 20,000 genes in the human genome), genetic analysis, and recommendations for treatment were completed in less than 35 days after surgery, ensuring that suggested therapies could begin within "a clinically acceptable time frame."

Timely administration of therapeutics is critical
Glioblastoma is an aggressive disease, with a median overall survival of only 15 months for newly diagnosed patients. One of the major difficulties in treating glioblastoma is its intrusive penetration into adjoining tissues, which prevents the complete surgical removal of the tumours from the brain, even with follow-up radiation and chemotherapy. As a result, nearly all glioblastomas recur. Patients whose brain cancer returns are often encouraged to enter experimental clinical trials. However, even on clinical trials, further progression of the disease is seen, on average, within 4 months.
"Notably, two of the patients experienced progression-free survival – meaning their tumour did not return or increase in size – for more than a year, with one of these patients progression-free at 21 months, three times longer than the time to progression on their previous therapy," said Dr. Michael D. Prados, the Charles B. Wilson Endowed Chair in Neurological Surgery at UCSF, and the study’s senior author.
Another major challenge in treating brain tumours is finding drugs that can penetrate the blood-brain barrier, which buffers the brain from the rest of the body’s blood-circulatory system. Located along small capillaries, the blood-brain barrier protects the brain from rapid changes in the body’s metabolic conditions and minimizes exposure to large molecules that are toxic to neurons in the brain.
The only FDA-approved standard-of-care drugs to treat glioblastoma are temozolomide, nitrosoureas, and bevacizumab.
In this study, more than 180 FDA-approved agents were reviewed, including all FDA-approved oncology drugs and a selection of repositioned agents that are approved by the FDA for other indications but show promising activity against cancer pathways. The tumor board considered the drugs supported by the genomic data for each patieunt, and discussed each drug’s ability to penetrate the blood-brain barrier, potential opportunities to combine treatments, drug-to-drug interactions and drug-safety profiles.
One of the patients was a 58-year-old woman with recurrent glioblastoma. Genomic sequencing showed several alterations with potential therapeutic relevance. Based on mutations in her NF1 and PALB2 genes, the UCSF Molecular Tumor Board recommended treatment with a combination of trametinib, olaparib and carboplatin. "This patient continued on treatment without disease progression (for more than) 665 days after surgery," according to the new paper, which adds, "Additional preclinical and clinical studies will be needed to determine the role of genomic context and combination therapy in the response observed for this patient."
"This precision-medicine study provides one of the first prospective demonstrations of using genome-wide molecular profiling to guide treatment recommendations for patients with recurrent glioblastoma within a clinically actionable time frame," said Dr. Michael Berens, TGen Deputy Director for Research Resources, and Professor and Director of TGen’s Cancer and Cell Biology Division.
"These findings provide a rationale and framework for larger prospective studies to further assess the efficacy of employing genomics-guided treatment for patients with recurrent glioblastoma," said Dr. Berens, one of the study’s authors.
TGen
tgen.org/home/news/2017-media-releases/tgen-ucsf-genomics-guided-brain-tumor-treatment.aspx#.WfJJcGKCxz8