Researchers at the University of Southampton have discovered specific markers on DNA that link the season of birth to risk of allergy in later life.
The season a person is born in influences a wide range of things: from risk of allergic disease, to height and lifespan. Yet little is known about how a one-time exposure like the season of birth has such lasting effects.

The Southampton study conducted epigenetic scanning on DNA samples from a group of people born on the Isle of Wight. They found that particular epigenetic marks (specifically, DNA methylation) were associated with season of birth and still present 18 years later. The research team was also able to link these birth season epigenetic marks to allergic disease, for example people born in autumn had an increased risk of eczema compared to those born in spring. The results were validated in a cohort of Dutch children.

John Holloway, Professor of Allergy and Respiratory Genetics at the University and one of the study’s authors, comments: “These are really interesting results. We know that season of birth has an effect on people throughout their lives. For example generally, people born in autumn and winter are at increased risk for allergic diseases such as asthma. However, until now, we did not know how the effects can be so long lasting.

“Epigenetic marks are attached onto DNA, and can influence gene expression (the process by which specific genes are activated to produce a required protein) for years, maybe even into the next generation. Our study has linked specific epigenetic marks with season of birth and risk of allergy. However, while these results have clinical implications in mediating against allergy risk, we are not advising altering pregnancy timing.”

Dr Gabrielle Lockett, of the University of Southampton and first author of the study, adds: “It might sound like a horoscope by the seasons, but now we have scientific evidence for how that horoscope could work. Because season of birth influences so many things, the epigenetic marks discovered in this study could also potentially be the mechanism for other seasonally influenced diseases and traits too, not just allergy.”

The team say that further research is needed to understand what it is about the different seasons of the year that leads to altered disease risk, and whether specific differences in the seasons including temperature, sunlight levels and diets play a part. More study is also needed on the relationship between DNA methylation and allergic disease, and whether other environmental exposures also alter the epigenome, with potential disease implications. University of Southampton

At age 56, Roma Jean Ockler was continually afflicted with sinus infections and pneumonia, and despite treatments, only seemed to be getting worse. For decades, immunologist Harry R. Hill, M.D., had seen patients like her. At the time he couldn’t have known that her family’s genetic information, combined with that of five other families from across the world, would classify a new disorder. Their subtype of common variable immunodeficiency disorder (CVID) results from mutations in IKAROS, a protein well known for its central role in immune cell development. The new findings make possible a definitive genetic diagnosis for this class of CVID, opening a door to precision medicine tailored to patients with the disorder.

The research was a collaboration between Hill and his colleagues Attila Kumánovics, M.D., Karl Voelkerding, M.D., Sarah South, Ph.D., Nancy Augustine, and Thomas Martins, M.S., from the University of Utah School of Medicine and the ARUP Institute for Clinical and Experimental Pathology at ARUP Laboratories in Salt Lake City, and 26 other scientists from institutions across the U.S. and Europe.

One of the most frustrating aspects of CVID is that it’s difficult to diagnose early before serious complications develop, says Hill. Occurring in about 1 in 20,000 people, the rare condition is actually a collection of disorders that cause a susceptibility to infection, as seen in Ockler’s case. Her illnesses worsened considerably over time but because doctors did not diagnose her, she was not given appropriate treatment. By the time she saw Hill for the first time, she had been through 17 years of sinus surgeries, pneumonias, and a life-threatening intestinal infection. Based on experience he prescribed an immunoglobulin regimen that has since quieted her symptoms.

The genetic causes of only about 15 percent of CVID cases have been identified, and Ockler did not have any of them. When Hill learned she had relatives with similar symptoms, he saw an opportunity to define her condition.

“We knew that if we could find the cause of her and her extended family’s disorder that we would have the chance to keep others from going through what she had,” says Hill, professor of pathology, paediatrics and medicine.

In collaboration with molecular pathologists Kumánovics and Voelkerding, they found that many of her relatives were missing one of two copies of a gene that codes for IKAROS. Meanwhile, Mary Ellen Conley, M.D., from The Rockefeller University, independently came to the same conclusion with her own patients. She connected with the Utah team and coordinated what would become an international effort revealing a total of six unrelated families who share similar sets of symptoms, and changes in the same gene, implicating IKAROS as the culprit behind their shared disorder. “Often research tries to answer a question that is brought up by the patients,” says Conley.      

Harry HillWhile some families had a change in just one DNA letter within the gene, others were missing a large piece, or all of it. Each of the mutations cripple a region required for IKAROS to function, a result confirmed by biochemical analysis, suggesting it cannot carry out its critical role in regulating immune B cell development. Indeed, as the experiments predicted, all six families have low B cell counts. In other words, their immune system is misconstructed, likely explaining why they also have low levels of infection-fighting antibodies (immunoglobulins).

Yet one of the most surprising findings, says Kumánovics, assistant professor of pathology, is that while some who carry the IKAROS mutations are prone to sickness, others appear to be healthy. He adds that understanding the biology that leads to this unexpected resilience could provide clues to overcoming the condition. “These rare patients don’t know how valuable they are. They are providing insights into how the immune system works,” he says. University of Utah

Researchers from Massachusetts Eye and Ear and Schepens Eye Research Institute have shown an association between a defective myogenic response — the regulatory increase or decrease in blood pressure to keep blood flow within the vessels of the retina constant — and early, accelerated development of retinopathy in patients with type 1 diabetes. These findings identify one mechanism to explain why some patients develop diabetic retinopathy sooner than others. Furthermore, the findings provide a target for future study, which may lead to therapies to delay or prevent the development of accelerated onset diabetic retinopathy.

“In patients with a normal myogenic response, the retinal vessels constrict when increased pressure arrives, to maintain constant blood flow and avoid damage to the smaller vessels in the retina,” said Mara Lorenzi, M.D., senior scientist at Massachusetts Eye and Ear/Schepens Eye Research Institute and a professor of ophthalmology, part-time at Harvard Medical School. “But we saw that, in about half of the diabetic patients in our study, the vessels did not constrict. In fact, paradoxically, some patients’ vessels dilated, and the blood flow to the retina was increased. This becomes a mechanism of damage for the small vessels, because these tiny, delicate capillaries are exposed to a big flow of pressure that can lead to the little haemorrhages and fluid leakage that are characteristic of diabetic retinopathy.”

The study included a small prospective study, in which the researchers closely followed 17 patients with type 1 diabetes whose myogenic responses had been measured four years prior. In approximately half of those patients, the researchers had observed defective myogenic responses. Five out of seven patients with defective myogenic responses developed accelerated diabetic retinopathy. The study also included a different group of patients with type 1 diabetes who had just developed retinopathy. Among these patients, the defective myogenic response was found only in those in whom retinopathy had appeared after a short duration of diabetes (fewer than 15 years of diabetes).

The most common diabetic eye disease and a leading cause of blindness in American adults, diabetic retinopathy occurs when blood vessels in the retina become damaged and leak fluid. Accumulation of fluid into the retina can lead to macular oedema . As the damage due to diabetes progresses, the vessels become occluded and can no longer carry blood. New blood vessels grow on the surface of the retina (proliferative retinopathy); but the new vessels are immature and may rupture impairing vision. Loss of visual acuity as a result of diabetic retinopathy is often the first warning sign for patients yet to be diagnosed with type 2 diabetes.

Currently, there are no treatments for diabetic retinopathy beyond controlling blood sugar and blood pressure levels. The new vessels of proliferative retinopathy can be treated with laser techniques, often at the expense of a portion of the retina. With the knowledge gained from the new studies, the researchers hope to target the defective myogenic response and develop therapies to prevent the development of accelerated diabetic retinopathy in this population. A larger study is needed to test the predictive capability of this abnormality. Massachusetts Eye and Ear

People with high levels of good cholesterol, or high-density lipoprotein, are not as safe from heart disease when high levels of a newly identified biomarker of inflammation in the arteries are also found in their bloodstream, according to a new study.

In the study of nearly 3,000 patients, researchers from the Intermountain Medical Center Heart Institute in Salt Lake City discovered that the presence of high levels of the biomarker glycoprotein acetylation, or GlycA, was associated with an increased risk of heart attack or stroke.

Inflammation of the artery walls is a contributing factor to heart attack and stroke because it increases the likelihood that plaque on the arterial walls will rupture, induce clot formation and block blood flow.

“We already know that HDL provides an anti-inflammatory effect on the arteries,” said Brent Muhlestein, MD, co-director of cardiovascular research at the Intermountain Medical Center Heart Institute. “But our research suggests there’s an interaction between GlycA and small HDL particles that reduces the anti-inflammatory capabilities of HDL and increases a person’s chances of having a heart attack or stroke.”

Using a test developed by LipoScience known as NMR spectroscopy, researchers measured lipoprotein particles and GlycA in 2,848 patients whose average age was 63 years old. Sixty-six percent of the patients were male and 65 percent had coronary artery disease.

“The results of our study reinforce the importance of the recommendations we offer to our patients working to reduce inflammation in their arteries by exercising regularly and eating heart-healthy foods,” said Dr. Muhlestein. “Some ways of increasing the HDL levels that will provide the anti-inflammatory protection include eating foods higher in Omega 3s and following the Mediterranean diet, which revolves around plant-based foods, healthy fats, and limited amounts of salt and red meat.”

Historically, C-reactive protein has been used as an indicator of inflammation in the body, and is predictive of future heart-related adverse events. Now, GlycA, a marker of inflammation identified through NMR, appears to show the same predictive ability.

However, researchers are currently seeking to determine if C-reactive protein and GlycA are completely independent of each other in terms of their impact on inflammation and heart disease.

“GlycA is a new particle we didn’t know much about, but now that we know there are epidemiologic associations, we need to look at additional ways to evaluate and understand the way it functions and interacts in the bloodstream,” said Dr. Muhlestein. Intermountain Medical Center Heart Institute

Researchers have identified a new set of genes that may be responsible for the two most common and disabling neurological conditions, stroke and dementia.

The study may help researchers better understand, treat and prevent ischemic and haemorrhagic stroke, and perhaps Alzheimer’s disease and other dementias.

Stroke is the leading neurological cause of death and disability worldwide. Previous studies have looked mainly at genes causing atherosclerosis and genes affecting the function of platelets and clotting processes as risk factors for ischemic stroke (clot obstructing blood flow to the brain). A different set of genes has been associated with haemorrhagic stroke (bleeding into the brain).

Researchers from Boston University School of Medicine looked for new stroke genes using genome wide association as well as meta-analysis. They identified a new gene called FOXF2 which increased the risk of having a stroke due to small vessel disease in the brain. No previous study has identified a gene for the common type of small vessel disease stroke although some genes associated with familial small vessel diseases such as CADASIL are known.

Sudha-Seshadri“Our research has identified a gene affecting another type of ischemic stroke, due to small vessel disease, and also suggests some genes may be associated with both ischemic and haemorrhagic stroke and may act through a novel pathway affecting pericytes, a type of cell in the wall of small arteries and capillaries. Unravelling the mechanisms of small vessel disease is essential for the development of therapeutic and preventive strategies for this major cause of stroke,” explained corresponding author Sudha Seshadri, MD, professor of neurology at BUSM.

According to the researchers small vessel disease not only causes stroke but is also a major contributor to dementia risk, and is associated with gait problems and depression. “Hence, it is exciting that we are beginning to better understand the cause of this very important and poorly understood type of stroke,” she added. Boston School of Medicine