Research Highlights 2016

Cancer Genetics of prostate cancer Family history is one of the few known risk factors for developing prostate cancer. This knowledge has led to the creation of the Tasmanian Familial Prostate Cancer Resource, a collection of blood and pathology samples from more than 50 Tasmanian families where prostate cancer is seen in multiple men across several generations. In 2016, we selected 10 families from this resource to identify rare genetic risk variants, those that occur in fewer than 2% of the general population. While these variants contribute to disease in just a small number of families, they are thought to increase a man’s risk by a large amount. We performed whole-genome sequencing in five families and have identified several rare variants that may be contributing to disease in these families and the wider Tasmanian population. We also checked these rare variants in a Seattle (US) familial prostate cancer resource and found that some of them may contribute to disease in these families too. The ultimate aim of our research is to identify rare variants that can be screened in Tasmanian men, especially those with a family history of prostate cancer. Variant carriers can then be tested for prostate cancer more frequently, as catching and treating the cancer early results in a higher chance of cure. (British Journal of Cancer, Human Molecular Genetics)

Inherited eye diseases Glaucoma We have identified new mutations in the MYOC gene that are important in glaucoma and have shown that genetic testing for this gene in families leads to early diagnosis and prevents vision loss. We identified a genetic mutation in patients with open-angle glaucoma and showed that a well-known glaucoma gene shows differential effects in males and females. As part of a very large international collaboration, we identified five new genes involved in angle closure glaucoma. In collaboration with researchers in the US, we identified a new gene for primary congenital glaucoma, which causes blindness in young children. This type of glaucoma was thought to mainly happen when a child inherited two bad copies of a gene (one from each parent), but this study showed that this is not always the case and that for patients with mutations in the TEK gene, one bad copy is enough to cause disease. Another paper published showed that there is overlap in genetic risk factors for glaucoma and agerelated macular degeneration. This has implications for predicting who is at risk of getting the diseases and also for the way we approach treatment in the future. (Experimental Eye Research, BMC Medical Genetics, Ophthalmology, Molecular Genetics & Genomic Medicine, Investigative Ophthalmology & Visual Science, Nature Genetics, Journal of Clinical Investigation, Scientific Reports) Age-related macular degeneration (AMD) We were part of the world’s largest ever genetic study of AMD, the most common cause of irreversible blindness in our community. Australian-based contributed the largest clinic-based cohorts to this collaboration, which identified 20 new genes that contribute to AMD. We also showed that

MENZIES INSTITUTE FOR MEDICAL RESEARCH BUILDING A HEALTHIER COMMUNITY

Associate Professors Kathryn Burdon and Alex Hewitt work with large international research collaborations that are making regular breakthroughs in eye disease genetics.

the dry and wet forms of AMD, although clinically distinct, are very similar at a genetic level. More work remains to be completed to understand what determines who will get wet or dry AMD and why. (Nature Genetics)

Diabetic Retinopathy New work built on several other papers from previous years and showed that a genetic variant in a microRNA gene is associated with diabetic eye and kidney disease, providing insight into why people often get both complications. (Acta Diabetologica, Diabetes and Vascular Disease Research) Paediatric (or congenital) Cataract We have a large project relating to the genetics of paediatric cataract, which is an important cause of blindness in children. A paper published in 2016 looked at the mechanism of a gene called EPHA2 and showed that it acts through several different pathways to cause cataract, dependent on the mutation that the patient has. Another paper expanded our understanding of the spectrum of mutations in a gene called CRYAA in paediatric cataract and showed that one mutation can cause multiple types of cataract. (Molecular Vision, BMC Research Notes)

Devil Facial Tumour Disease The Tasmanian devil immunology team has recently demonstrated that immune checkpoint molecules that exist in humans are also present in devils. This may play a role in the ability of the Tasmania Devil Facial Tumour to evade the devil’s immune system. The identification of PD-1 molecule in the Tasmanian devil is a substantial advance in marsupial immunology as surprisingly little is known about the potential for cancer immunotherapies in the field of veterinary medicine. This paper is the first to explore the relevance of key immune checkpoints in marsupials. The team also provided the first evidence that some wild Tasmanian devils are capable of recovering from DFTD. (Frontiers in Immunology, Biology Letters)

Would you like to know more? If you would like more information about our current research projects at the Menzies Institute for Medical Research: www.menzies.utas.edu.au Phone: +61 (0)3 6226 7700 Email: enquiries@menzies.utas.edu.au www.menzies.utas.edu.au www.facebook.com/MenziesResearch @ResearchMenzies www.linkedin.com/company/menzies-institute-formedical-research If you would like information on how you can donate to medical research at Menzies, please contact the Institute Advancement Manager on +61 (0)3 6226 4236 or email menzies.advancement@utas.edu.au. ABN 30 764 374 782 – University of Tasmania

Cover image: Dr Catherine Blizzard is the senior author on research published in 2016 which provided new insight into why the motor system fails in motor neurone disease. Photograph by Peter Mathew

menzies.utas.edu.au

were consistent across regions of the world and over a 20-year period. We found that the reason women have worse outcomes from stroke than men is mainly due to the fact that they are older when they have a stroke and they appear to have more severe strokes. Treatment in hospital after stroke is about the same for men and women, suggesting that better stroke outcomes may be possible through improvements in general health care for the elderly and by identifying new ways to reduce the severity of strokes. (Circulation: Cardiovascular Quality and Outcomes)

Research Highlights 2016 The Menzies Institute for Medical Research exists to perform internationally significant medical research leading to healthier, longer and better lives for Tasmanians. We have been making discoveries to improve the health of our community since our establishment in 1988. Once again in 2016 we saw some remarkable research that will advance our progress towards better health. Menzies research is cross-disciplinary but is organised into five themes which reflect the burden of disease in the Tasmanian community. The research themes are: • Public Health and Primary Care • Musculoskeletal Health and Diseases • Neurodegenerative Diseases/Brain Injury • Cardio-metabolic Health and Diseases • Cancer, Genetics and Immunology

Blood pressure Professor Bruce Taylor was the lead author on work that showed the significance of latitude in the timing of the onset of MS.

Multiple sclerosis Latitude link This large international study led by Menzies found that the age of onset of MS symptoms is strongly linked to latitude. The average age at which symptoms first appeared was around 32. But after taking account of potentially influential factors, it emerged that each 10-degree increase in latitude was associated with a 10-month earlier onset of symptoms, with those patients furthest from the equator experiencing symptoms almost two years earlier than those closest to the equator. More than 80% of the patients in the study were from the northern hemisphere, with about two-thirds (67%) from Europe. Around one in six (just under 16%) were from Australia, including about 300 people with MS from Tasmania. (Journal of Neurology Neurosurgery & Psychiatry) Genetics and Epstein-Barr Virus This large collaborative piece of research links two of the major causes of MS – the immune response to EpsteinBarr Virus (EBV) infection and genetic risk. The work used Australian and international data to identify the susceptibility genes associated with a differential immune system response to EBV infection. The research forms the basis for a large international collaborative research group to study the area further and utilise similar techniques to study larger cohorts and different viruses. (Multiple Sclerosis Journal) Transcranial magnetic stimulation We are investigating the potential of transcranial magnetic stimulation as an MS therapy. As part of this project Menzies research was published demonstrating the effect of magnetic patterns on glial cells in the central nervous system. (Frontiers in Neural Circuits)

Obesity

Menzies Director Professor Alison Venn leads the Childhood Determinants of Adult Health study and the INVEST study, which is examining obesity surgery in Tasmania.

The INVEST project (Investigating Obesity Surgery in Tasmania) is being conducted in partnership with researchers, government policy makers and clinicians to help develop better treatment services for patients with obesity and obesity-related disease. Members of the project team have investigated patient experiences and identified reasons people seek obesity surgery, highlighting the

Research led by Dr Seana Gall is examining data from 16,000 cases of stroke compiled in 14 different studies; A new health economics model for osteoporosis developed by Dr Lei Si will help decision-makers identify cost-effective ways to prevent fractures; Dr Xingzhong Jin is one of the lead authors on a study showing that Vitamin D is not helpful in reducing pain or slowing cartilage loss in knee osteoarthritis.

importance of health professionals understanding what motivates patients to take this step. This knowledge helps health professionals to manage patients’ expectations about surgery outcomes and to plan relevant treatment and supports. Cost and quality-of-life outcomes were investigated in a group of surgery recipients. We also reviewed the rates of re-operations for complications after secondary obesity surgery. We now know the broader costs to the individual and society of obesity management and surgery have not been well measured. As a result, the availability and quality of information to those in charge of allocating healthcare resources is limited. The project is continuing. (Obesity Surgery, Bariatric Surgical Practice and Patient Care, Health Expectations, Obesity Reviews)

Mental health The importance of lifestyle in mental health had not been properly explored previously, despite recognition of its importance in the prevention of cardiovascular disease. Our study looked at the impact of lifestyle, measured using information on a range of health behaviours, on depression and the impact of depression on lifestyle – the first time the association has been examined from both sides. Researchers examined multiple health behaviours and found that people with a history of depression were 25% less likely to improve their lifestyle and 46% more likely to have a worsening of lifestyle over the five-year period than those without a history of mood disorder. We also found that healthy lifestyles strongly protected against new episodes of mood disorder over the five-year period independent of a wide range of potentially confounding factors. There was a 22% reduction in the risk of suffering a new episode of mood disorder per healthy behaviour, which is similar to effects seen for pharmacological interventions. (Psychological Medicine)

Cardiovascular disease Child muscular fitness and adult metabolic syndrome This study aimed to determine whether childhood muscular fitness (including strength, endurance and power) independently predicts metabolic syndrome in adulthood. Metabolic syndrome is a term to describe the

cluster of conditions associated with the development of cardiovascular disease and type 2 diabetes. Using data from the Childhood Determinants of Adult Health study, we followed up 737 participants who had muscular fitness measures taken in 1985 at age 9, 12 or 15 and who attended clinics 20 years later when measures of metabolic syndrome were collected. We found that the measures of childhood muscular fitness predicted adult metabolic syndrome, independent of measures of cardio-respiratory fitness in childhood. This means that the promotion of muscular fitness among children might provide additional protection against metabolic syndrome in adulthood. (Medicine & Science in Sports & Exercise)

Hospital Re-admissions This work, through the Tasmanian Study of Heart failure Re-admission Prevention, has defined an effective means of identifying people at risk of re-admission to hospital after heart failure, meaning the intensity of intervention can be targeted according to risk. Heart failure is the leading cause of hospitalisation and rehospitalisation among adults aged over 65. Short-term re-admissions from heart failure place a burden on the healthcare system and increase mortality risks for patients. Our predictive model of 30-day re-admission or death in heart failure, developed from an Australia-wide sample of heart failure patients, has for the first time combined both clinical and non-clinical factors. The work has international appeal as the first study to identify high risk individuals by integrating the social determinants of health into the research. (Journal of the American Medical Association Cardiology)

Stroke Stroke affects more women than men, and these women are at a greater risk of dying or suffering ongoing disability after stroke than men. Menzies researchers are leading an international team of investigators in one of the world’s largest studies of stroke. Data has been gathered from over 16,000 strokes from 14 different studies. Through analysis of this data we have found that women are about 30% more likely to be deceased and about 30% more likely to be disabled than men one year after stroke. The results

Our work in blood pressure continues to be informed by our on-site clinic for people with difficult to manage blood pressure as well as our own research in collaboration with colleagues around the world. Our research group was part of The Lancet Commission on Hypertension, an international collective to identify actions that will improve the management of blood pressure both at population and individual level. We led an international task force on the validation of blood pressure monitors that appeared in the top European cardiology journal, and we expect this work will lead to better methods of measuring blood pressure – a key problem in the field. We found a new way for doctors to quickly assess patient home blood pressure diaries to determine the true level of underlying blood pressure. This paper was published in the leading US journal dedicated to general practice medicine. We also contributed to a hot topic – the cardiovascular effects of vitamin D supplementation. All expectations were that vitamin D would be beneficial to cardiovascular health but in fact the clinical trial results clearly showed no benefit in lowering blood pressure or improving arterial stiffness. (European Heart Journal, Journal of the American College of Cardiology, Annals of Family Medicine)

Motor neurone disease

reducing knee pain or slowing cartilage loss, even in those who are vitamin D deficient. The finding can be quickly translated to clinical practice, where it will prevent patients from spending money on a therapy now proven to be ineffective. (Journal of the American Medical Association)

How much physical activity? Research matched musculoskeletal health indicators in middle aged women (aged 36-57) with physical activity and sedentary time. We found total physical activity was beneficially associated with improvement in bone mineral density in femoral neck, leg muscle strength and ‘timed up and go test’ (a test used to assess mobility requiring static and dynamic balance) measurements. Similarly, moderate to vigorous activity was associated with positive results but light physical activity or sedentary time was not associated with any outcomes. The research can be used to inform programs designed to improve habitual physical activity and to inform public health advice on women’s bone health. (Journal of Bone and Mineral Research) The cost of osteoporosis We have constructed and validated a new osteoporosis health economics model using state-of-the-art techniques and the most up-to-date clinical data to overcome the shortcomings of previous models. The model looked at the cost-effectiveness of screening and treatment for osteoporosis in Chinese post-menopausal women, and this will now be adapted to the Australian setting. The model helps decision-makers identify a cost-effective means to prevent future osteoporotic fractures. It has been applied to answer clinical and economic research questions, such as the number and cost of osteoporotic fractures in China, the remaining lifetime and 10-year fracture risks in the Chinese population and to evaluate the cost-effectiveness of the osteoporosis prevention drug raloxifene. (Osteoporosis International)

Meticulous research produced a convincing new insight into why the motor system fails in motor neurone disease. Researchers investigated whether the main protein, TDP43, known to cause the disease may be affecting the way neurons communicate. To investigate this they designed a laboratory model to visualise neurons as pathology in the protein developed. They found that mutant TDP-43 protein had a significant pathological effect on the generation and pruning of dendritic spines, the microscopic synapses that connect neurons, which has severe consequences for neuronal function. This was one of the first studies to investigate synaptic and functional changes driven by the protein TDP-43, and indicates that there is an early route by which altered TDP-43 function can cause the neural dysfunction that causes MND. The finding is significant not only for MND but also for understanding the fundamental function of the brain. (Cerebral Cortex)

Osteoarthritis and osteoporosis Vitamin D is not the answer Through the largest and most rigorous randomised trial so far of the effects of Vitamin D on knee osteoarthritis we showed clearly that vitamin D provided no help in

Professor James Sharman and Dr Martin Schultz are contributing to better understanding internationally of how blood pressure should be managed.