Case Western Reserve University is part of a landmark study that has discovered four novel gene variations which are associated with blood pressure. The 19-site meta-analysis, involving nearly 30,000 African-Americans, also found that the set of genetic mutations are also associated with blood pressure across other populations.
Epidemiology and biostatistics professor Xiaofeng Zhu, PhD, is co-senior author of the paper. The Continental Origins and Genetic Epidemiology Network (COGENT) consortium conducted the research, which is the largest genome-wide association study of blood pressure in individuals of African ancestry. Most gene discovery studies to date have been performed using individuals of European ancestry. Previous genome-wide association studies using samples from individuals of African descent failed to detect any replicable genes associated with blood pressure.
‘In addition to their disproportionate suffering, hypertension occurs earlier in life for African-Americans compared to individuals of other ancestries,’ Zhu explained. ‘Therefore, it is important to study this population to better understand genetic susceptibility to hypertension.’
Zhu and his colleagues also confirmed that previous findings regarding other genes whose presence correlates with increased hypertension risk.
‘Although it is unknown how the genes regulate blood pressure,’ Zhu added, ‘our findings contribute to better understanding of blood pressure pathways that can lead to future development of drug target for hypertension and may guide therapy for clinical care.’
Experts estimate genetic make-up accounts for roughly 40-50 percent of individuals’ susceptibility to hypertension. Other factors associated with the disease include lifestyle, diet, and obesity. Compared to Americans of European-ancestry, African-Americans’ increased hypertension prevalence contributes to a greater risk of stroke, coronary heart disease, and end-stage renal disease.
‘We anticipated that individuals of African ancestry share similar biology to other populations. However, differences in genomic make-up between African ancestry and other populations have uncovered additional genes affecting blood pressure, in addition to genetic variants that are specific to individuals of African ancestry,’ said Nora Franceschini, MD, MPH, nephrologist and research assistant professor of epidemiology at the University of North Carolina at Chapel Hill and first author on the paper.
The next phase of study involving the newly discovered gene mutations will investigate their function using human blood samples at the molecular level. Zhu and his colleagues have begun conducting additional research to determine whether the newly identified genes respond to existing hypertension medications. Individuals typically respond differently to a given medication depending on which gene mutation they carry. The more information researchers gather, the greater opportunity clinicians will have prescribed the drug that is most efficacious based on the patient’s specific mutation.
‘The research findings do not have immediate implications for treatment, but the hope is that discovering genes associated with disease risks will bring scientists closer to biological pathways and may suggest useful targets for new treatments,’ said geneticist Brendan J. Keating, DPhil, one of co-senior authors of the paper, of The Center for Applied Genomics at The Children’s Hospital of Philadelphia and faculty at the Department of Pediatrics at the University of Pennsylvania. Case Western Reserve University School of Medicine

For the first time, researchers have created a model that could help unlock what causes adenomyosis, a common gynaecological disease that is a major contributor to women having to undergo hysterectomies.

In a two-step process, a team led by Michigan State University’s Jae-Wook Jeong first identified a protein known as beta-catenin that may play a key role in the development of the disease. When activated, beta-catenin causes changes in certain cells in a woman’s uterus, leading to adenomyosis.

Then Jeong, an associate professor in the College of Human Medicine’s Department of Obstetrics, Gynecology and Reproductive Biology, created a mouse model that may reveal useful targets for new treatments.

‘Progress in the understanding what causes adenomyosis and finding potential drug treatments has been hampered by the lack of defined molecular mechanisms and animal models,’ Jeong said.

‘These findings provide great insights into our understanding of the beta-catenin protein and will lead to the translation of animal models for the development of new therapeutic approaches.’

The disease occurs when the inner lining of the uterus (endometrium) breaks through the muscle wall of the uterus (myometrium). Symptoms of the disease include menstrual bleeding, chronic pelvic pain and infertility. Most women with the disease require surgery, and 66 percent of hysterectomies are associated with it.

‘This research offers hope to the millions of women who have adenomyosis and holds promise that a cure, besides hysterectomy, is on the horizon,’ said Richard Leach, chairperson of the Department of Obstetrics, Gynecology and Reproductive Biology. Michigan State University

Scientists have identified the genetic cause of a rare skin condition that causes the hands and feet to turn white and spongy when exposed to water.
The study, led by researchers from Queen Mary, University of London, has provided scientists with an insight into how the skin barrier functions and could help with research into a variety of conditions.
Diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) is a rare condition in which individuals have thickened, yellowish skin over their palms and soles, thickened nails and suffer from excessive sweating. When their hands and feet are exposed to water, the skin quickly turns white and spongy and individuals are prone to fungal infections.
While prevalence in the general population is estimated at one in 40,000 it is much higher in northern Sweden (up to one in 200 people), where a single ancestral genetic mutation is believed to have originated and then subsequently passed down from generation to generation.
A team led by David Kelsell, Professor of Human Molecular Genetics at Queen Mary studied DNA from a number of families of British and Swedish origin in which the skin condition is present. Using high throughput DNA sequencing methods they were able to pin down the underlying cause of the condition to mutations in the AQP5 gene, which encodes a water channel protein known as aquaporin 5. All individuals who have inherited an AQP5 mutation will present with this rare skin condition.
Professor Kelsell, from the Blizard Institute at Barts and The London School of Medicine and Dentistry, Queen Mary, said: ‘Aquaporins are a family of proteins known as ‘the plumbing system for cells’ as they form pores which allow water to flow through cells rapidly.
‘We knew aquaporin 5 was present in high amounts in the sweat glands, salivary glands and tear ducts – routes by which the body loses water. Here we’ve demonstrated it is also found in the skin, with higher amounts in the hands and feet.’
Co-author Dr Diana Blaydon, also from the Blizard Institute, explained: ‘The AQP5 gene mutation appears to result in a protein that has a wider channel than usual, forming a bigger pore in the cell membrane allowing more water to permeate it.’
Further work is needed to understand exactly how the mutations identified and the associated changes in the skin barrier lead to NEPPK .
Professor Kelsell added: ‘While we’ve studied aquaporins in the skin, these results also give us an idea of what might be happening in internal aquaporins, which are found in structures throughout the body, including the kidneys, cornea and lungs.’ Queen Mary, University of London

A large-scale, international study on the genes involved in epilepsy has uncovered 25 new mutations on nine key genes behind a devastating form of the disorder during childhood.
Among those were two genes never before associated with this form of epilepsy, one of which previously had been linked to autism and a rare neurological disorder, for which an effective therapy already has been developed.
The findings suggest a new direction for developing genome-wide diagnostic screens for new-borns to identify who is at risk for epilepsy and potentially to develop precise therapies for the condition.
The results are the first to emerge from a set of epilepsy-genetics projects known as EPGP and Epi4K, which were launched by the National Institutes of Health in 2007 and 2012, respectively, and involve more than 40 institutions on three continents. While UC San Francisco and Duke University serve as the administrative hubs, the projects involve a team of nearly 150 scientists across 25 specialities, in the hopes of generating this type of advance on the intractable disease.
‘The limitations of what we currently can do for epilepsy patients are completely overwhelming,’ said Daniel Lowenstein, MD, a UCSF neuroscientist and renowned epilepsy expert who, along with Ruben Kuzniecky, MD, from New York University, is overseeing the Epilepsy Phenome/Genome Project (EPGP). ‘More than a third of our patients are not treatable with any medication, so the idea of finding specific drug targets, instead of a drug that just bathes the brain and may cause problems with normal brain function, is very appealing.’
The global team started with the most severe forms of the disorder, known as epileptic encephalopathies (EE), which affect roughly one in 2,000 children, often before their first birthdays. Many of these children also experience other severe disabilities, including autism or cognitive dysfunction. Whether the epilepsy contributes to those, or vice versa, is being addressed in a parallel study.
‘We knew there was something happening that was unique to these kids, but we had no idea what that was,’ said Elliott Sherr, MD, PhD, a UCSF physician-scientist who is the principal investigator of the Epi4K Epileptic Encephalopathy project and who developed this group of patients within EPGP. ‘In a common disease like cystic fibrosis, you’re likely to see more than one child in a family affected. In this case, it is very rare to have more than one person in the entire family with this condition.’
That lack of clear, inherited links to the disease led them to propose that the condition was being caused by de novo, or brand new, mutations on certain genes.
They set out to test that hypothesis.
The team identified children with two classic forms of EE – infantile spasms and Lennox-Gastaut Syndrome – in which no other family member was affected. They excluded children who had identifiable causes of epilepsy, such as strokes at birth, which are a known risk for this group of disorders. Of the 4,000 patients whose genomes are being analysed in the Epi4K, 264 children fit that description.
The Epi4K sequencing team, led by David Goldstein, PhD, at Duke, ran a genetic scan on the children and their parents, which they compared to thousands of people of similar heritage without epilepsy. They used a cutting-edge new technique called exome sequencing to focus on the exome – the 2 percent of our genetic code that represents active, protein-making genes. Those 25,000 genes are considered to be the code for what makes us unique, including disease mutations.
The genetic analysis revealed 439 new mutations in the children, with 181 of the children having at least one. Nine of the genes that hosted those mutations appeared in at least two children with EE and five of those had shown up in previous, smaller EE studies. Of the four others, two may have been coincidental, the researchers found. But two new genes never before associated with EE – known scientifically as GABRB3 and ALG13 – each appeared with less than a one-in-40-billion statistical chance (p = 4.1×10-10) of being connected to EE by coincidence.
The findings implicated GABRB3, for the first time, as a single-gene cause of EE, and offered the strongest evidence to date for the gene’s role in any form of epilepsy, Sherr said. Knowing this about GABRB3, which is also involved with Angelman’s Syndrome, also offers the possibility that children with mutations only in this gene might benefit from the existing therapy for Angelman’s.
Another new gene, ALG13, is key to putting sugars on proteins, which points to a new way of thinking about the causes of and treatment for epilepsy.
‘The take-home is that a lot of these kids have genetic changes that are unique to them,’ Sherr said. ‘Most of these genes have been implicated in these or other epilepsies – others were genes that have never been seen before – but many of the kids have one of these smoking guns.’ University of California – San Francisco