Researchers have identified a type of human leukocyte antigen (HLA) that is associated with the skin disease bullous pemphigoid (BP) in diabetic patients administered with DPP-4 inhibitory drugs.
DPP-4 inhibitor (DPP-4i) is widely used to treat type 2 diabetes, but increased cases of bullous pemphigoid (BP) have been reported among patients taking the medicine. BP is the most common autoimmune blistering disorder, characterized by itchy reddening of the skin as well as tense blisters over the whole body. Afflicted patients, mostly elderly, suffer from autoimmune attacks on a type of collagen in skin, making it hard to cure and compromising their quality of life. Previously, no risk factor triggering BP in diabetic patients administered with DPP-4i had been identified.
BP is classified into two types: inflammatory and non-inflammatory, the latter of which is found more in diabetic patients administered with the drug. The research team, including Dr. Hideyuki Ujiie of Hokkaido University Hospital, examined 30 BP patients administered with DPP-4i, and investigated their symptoms and autoantibodies to group them as inflammatory or noninflammatory.
The researchers then analysed human leukocyte antigen (HLA) genes of the 30 patients to identify their white blood cell type since HLA genes are known to be involved in various immune diseases. To compare, the team also analysed the HLA of 72 BP patients who had not been administered with DPP-4i and 61 diabetic patients who were using the drug but not affected by BP. Their findings were compared with the HLA genes of 873 Japanese from the general population.
According to the results, 70 percent of the 30 BP patients administered with DPP-4i fell into the non-inflammatory type with less reddening of the skin (erythema). HLA analyses found 86 percent of the non-inflammatory BP patients administered with DPP-4i had an HLA gene called “HLA-DQB1*03:01.” The rate of having the HLA gene was much higher than was detected among the general population (18 percent) and non-BP type-2 diabetic patients administered with DPP-4i (31 percent). Meanwhile, 26 percent of BP patients who were not administered with the drug had the same HLA gene.
The findings show HLA-DQB1*03:01 is not linked to ordinary BP nor type-2 diabetes, but is closely associated with the development of BP among DPP-4i takers. “However, as the probability of patients exposed to DPP-4i to develop BP remains unclear, further research investigating a much larger number of cases is needed,” says Hideyuki Ujiie.
“Our results suggest people with HLA-DQB1*03:01 have a higher risk of developing BP when exposed to DPP-4i than those without the HLA gene. The gene could serve as a biomarker to help estimate the risk of developing BP when patients are administered with DPP-4i. The mechanism that connects the HLA gene and BP needs to be addressed to help prevent the development of the disease,” Ujiie added.
ScienceDailyhttps://tinyurl.com/y9u48zv3 

A group of investigators from Mayo Clinic and multiple academic research centres in Italy have identified a genetic model for predicting outcomes in patients with primary myelofibrosis who are 70 years or younger and candidates for stem cell transplant to treat their disease.
“Myelofibrosis is a rare type of chronic leukemia that disrupts the body’s normal production of blood cells,” says Dr. Tefferi. “Prior to this study, the most comprehensive predictive model for outcomes in myelofibrosis, utilized mostly clinical variables, such as age, hemoglobin level, symptoms, white blood cell count and the percentage of immature cells in the peripheral blood.”
Dr. Tefferi says he and his colleagues incorporated new genetic tests in the model for gene mutations including JAK2, CALR, and MPL, which are known to drive myelofibrosis. He says the new model also tests for the presence or absence of high-risk mutations such as ASXL1 and SRSF2. “Our model is also unique in that we developed it for patients who are age 70 years or younger who may still be candidates for a stem cell transplant to treat their disease,” Dr. Tefferi says.
Researchers studied 805 patients with primary myelofibrosis who were 70 years of age or younger. Patients were recruited from multiple centres in Italy and from Mayo Clinic in Minnesota. The Italian and Minnesota groups formed two independent learning and validation cohorts. “We were surprised by how similar the predictive models performed in two completely separate patient databases,” Dr. Tefferi says.
Dr. Tefferi says that genetic information is increasingly being used as a prognostic biomarker in patients with primary myelofibrosis and he anticipates the potential use of such an approach along with relevant clinical, cytogenetic and mutational data for other hematologic and non-hematologic cancers.
Mayo Clinic Cancer Centerhttps://tinyurl.com/y7zlxtqz

Clearing a major hurdle in the field of microbiome research, Harvard Medical School scientists have designed and successfully used a method to tease out cause-and-effect relationships between gut bacteria and disease.
The team says the approach could propel research beyond mere microbiome-disease associations and elucidate true cause-effect relationships.
The experiments, conducted in mice, also identify a previously unknown gut microbe that tames intestinal inflammation and protects against severe colitis. The researchers say the finding makes a strong case for testing the newly identified gut bacterium as a probiotic therapy in people with inflammatory bowel disease, a constellation of conditions marked by chronic inflammation of the intestines and estimated to affect up to 1.3 million people in the United States, according to the Centers for Disease Control and Prevention.
The approach uses a sort of “microbial triangulation.” It mimics the principles of classic maritime navigation or, in more modern terms, tracking the location of a mobile phone by verifying data from multiple sources—but instead of stars or cell phone towers, the researchers are homing in on intestinal bugs. Based on the method of elimination, the technique involves the gradual narrowing down of bacterial species to identify specific microbes that modulate the risk for specific diseases. In the current study, researchers adapted the principles to identify beneficial, protective bacteria.
“Our approach can help scientists find the proverbial needles in a ‘haystack’ of thousands of microbes that are currently thought to modulate health,” said investigator Dennis Kasper, professor of microbiology and immunobiology at Harvard Medical School. “If the field is to move past associations—the Achilles’ heel in microbiome research—we need a system that reliably teases out causative relationships between gut bacteria and disease. We believe our method achieves that,” added Kasper, who is also the Harvard Medical School William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital.
Over the last decade, study after study has identified thousands of commensal microbes—those residing innocently in our bodies—and catalogued observations of possible links between groups of microbes and the presence or absence of a panoply of diseases, including diabetes, multiple sclerosis and inflammatory bowel disease. Yet, scientists don’t know whether and how the presence of specific microbes—or fluctuations in their numbers—affects health. It remains unclear whether certain microbes are innocent bystanders, mere markers of disease, or whether they are active agents, causing harm or providing protection against certain ailments.
The holy grail of this work would be not to merely define whether a microbe fuels or minimizes the risk for a given disease but to discover microbes and microbial molecules that can be used therapeutically.
“The ultimate goal is to clarify the mechanisms of disease and then identify bacterial molecules that can be used to treat, reverse or prevent it,” said study lead author Neeraj Surana, Harvard Medical School instructor in pediatrics and an infectious disease specialist at Boston Children’s Hospital.
For their study, Kasper and Surana compared the gut microbiomes of several groups of mice that harboured different populations of intestinal bacteria.
The researchers started out with two groups of mice. One group had been bred with human gut microbiomes—housing intestinal bacteria normally found in human intestines. The other group had been bred to harbour normal mouse microbiomes. When researchers gave the animals a chemical compound that triggered intestinal inflammation, or colitis, mice that harboured human intestinal microbes were protected from the effects of the disease. Mice whose guts harboured typical mouse bacteria, however, developed severe symptoms.
Next, the researchers housed all mice in the same living space. Sharing living space for as briefly as one day led to noticeable changes in how the animals responded to disease. Mice that had been originally protected from colitis started showing more serious signs of it, while colitis-prone mice grew increasingly resistant to the effects of the condition and developed milder symptoms—a proof-of-principle finding which shows that exchange of intestinal bacteria through shared living space can lead to changes in the animals’ ability to cope with the disease.
The disease-modulating microbe would be lurking amid the hundreds of bacterial species present in all mice. But given that each mouse group harboured between 700 and 1,100 bacterial species in their guts, how could scientists identify the one that truly mattered in colitis? The team began by analysing the intestinal makeup of each one of the mouse groups, comparing their microbial profiles before and after they shared a living space. To “triangulate” the suspect’s identity, scientists looked for microbes that were either scarce or abundant, tracking with colitis severity. In other words, the numbers of the causative microbe would either go up or down with disease severity, the scientists reasoned. Only one such microbial group fit the profile—a bacterial family known as Lachnospiraceae, commonly found in human intestines as well as the guts of other mammals.
To pinpoint the one organism within the Lachnospiraceae family that regulates response to colitis, the researchers isolated one bacterial species and gave it to colitis-prone mice. To compare its effects against other microbes, they also gave the animals organisms from different bacterial families. The only bacterium that protected colitis-prone animals from the ravages of the disease was a never-before-described microbe that the researchers had isolated from the guts of mice seeded with human feces, the animals that had harboured human microbiomes. The microbe was notably absent from mice with mouse microbiomes. Because of its immune-protective properties, Kasper and Surana christened the newly identified organism Clostridium immunis.
The isolation of the disease-modifying microbe makes a powerful case for testing it as therapy in people with inflammatory bowel disease, the researchers said.
Harvard Medical Schoolhttps://tinyurl.com/yawe5qvh

A gene which could play a role in causing the most severe cases of club foot has been identified by scientists at the University of Aberdeen.
Clubfoot is a lower leg abnormality, where babies are born with the foot in a twisted position, facing inwards and upwards rather than flat to the floor.  It is quite common, affecting about 1 baby in every 1,000 born in the UK.  Of those, 1,000 about half have the condition in both feet.
The causes of clubfoot are very poorly understood, though it sometimes runs in families and it is known that genes are involved.
Experts believe the condition is a neuro-muscular problem – a result of muscle weakness in the legs during development. However it is difficult to pinpoint the causes because there are so many different things that can cause muscle weakness.
The condition requires lengthy treatment involving manipulation, putting the feet in a cast (called the Ponseti method) an operation and then a requirement to wear specialised boots joined together by a metal bar at night until the age of four or five years old.
In severe cases, which are often associated with failure of the nerves to calf muscles, even after this treatment the foot can bend back, meaning a more invasive surgery is required.
The Aberdeen team believe they may have identified a gene in a mouse model which is linked to the more serious cases of clubfoot in humans.
The gene (Limk1) is required for normal nerve growth and has shown to be part of a pathway of genes, one of which is already known to be linked to clubfoot in mice.
Professor Martin Collinson, a geneticist from the University of Aberdeen, and leader of the study says: “This is, hopefully, another piece in the puzzle of what causes clubfoot in humans. Our hypothesis is that probably for most human clubfoot patients, it’s not just one gene that goes wrong, there are probably predisposed mutations in several genes in these pathways and they add up to eventually cause muscle weakness.
“The next stage is to look at DNA samples taken from human clubfoot patients and screen them to see if there are mutations in these pathways.
“Club foot is commonly treated successfully using the Ponseti method but it may be that the feet of children with these gene deformations will just revert back once treatment is finished. In theory if we could screen children for these genes before treatment starts, then they could avoid years of unnecessary interventions.”
University of Aberdeenwww.abdn.ac.uk/news/11665/

Researchers have identified specific genes that may trigger the development of sleep problems, and have also demonstrated a genetic link between insomnia and psychiatric disorders such as depression, or physical conditions such as type 2 diabetes. The study was led by Murray Stein of the University of California San Diego and the VA San Diego Healthcare System.
Up to 20 percent of Americans and up to 50 percent of US military veterans are said to have trouble sleeping. The effects insomnia has on a person’s health can be debilitating and place a strain on the healthcare system. Chronic insomnia goes hand in hand with various long-term health issues such as heart disease and type 2 diabetes, as well as mental illness such as post-traumatic stress disorder (PTSD) and suicide.
Twin studies have in the past shown that various sleep-related traits, including insomnia, are heritable. Based on these findings, researchers have started to look into the specific gene variants involved. Stein says such studies are important, given the vast range of reasons why people suffer from insomnia, and the different symptoms and varieties of sleeplessness that can be experienced.
"A better understanding of the molecular bases for insomnia will be critical for the development of new treatments," he adds.
In this study, Stein’s research team conducted genome-wide association studies (GWAS). DNA samples obtained from more than 33,000 soldiers participating in the Army Study To Assess Risk and Resilience in Service members (STARRS) were analysed. Data from soldiers of European, African and Latino descent were grouped separately as part of efforts to identify the influence of specific ancestral lineages. Stein and his colleagues also compared their results with those of two recent studies that used data from the UK Biobank.
Overall, the study confirms that insomnia has a partially heritable basis. The researchers also found a strong genetic link between insomnia and type 2 diabetes. Among participants of European descent, there was additionally a genetic tie between sleeplessness and major depression.
"The genetic correlation between insomnia disorder and other psychiatric disorders, such as major depression, and physical disorders such as type 2 diabetes suggests a shared genetic diathesis for these commonly co-occurring phenotypes," says Stein, who adds that the findings strengthen similar conclusions from prior twin and genome-wide association studies.
Insomnia was linked to the occurrence of specific variants on chromosome 7. In people of European descent, there were also differences on chromosome 9. The variant on chromosome 7, for instance, is close to AUTS2, a gene that has been linked to alcohol consumption, as well as others that relate to brain development and sleep-related electric signalling.
"Several of these variants rest comfortably among locations and pathways already known to be related to sleep and circadian rhythms," Stein elaborates. "Such insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease."
EurekAlertwww.eurekalert.org/pub_releases/2018-03/s-csc030818.php