A genetic discovery will make treatment for Crohn’s disease and ulcerative colitis safer, by identifying patients who are at risk of potentially deadly drug side effects.
A ground-breaking and large-scale NHS research collaboration, led by the University of Exeter and the Royal Devon & Exeter NHS Foundation Trust, has discovered a gene mutation that allows the identification of patients at risk of a drug side effect, allowing clinicians to tailor alternative treatments to these individuals.
This finding will reduce the risk of drug side effects caused by treatment with thiopurines (consisting of azathioprine and mercaptopurine). This group of drugs is commonly used for the treatment of autoimmune and inflammatory diseases.
Crohn’s disease and ulcerative colitis (collectively known as inflammatory bowel disease –IBD) are incurable lifelong conditions that affect approximately 1 in 150 people in the UK. The main symptoms are urgent diarrhoea, often with rectal bleeding, abdominal pain, profound fatigue and weight loss. The condition disrupts people’s education, working, social and family life. Drugs to suppress the immune system are the mainstay of treatment, however more than half of patients with Crohn’s Disease and about 20 per cent of patients with ulcerative colitis will require surgery at some point. The lifetime medical costs associated with the care of a person with IBD are similar to the costs of treating diabetes or cancer.
About a third of patients with IBD are treated with a thiopurine drug, however, approximately 7 per cent of patients develop an adverse reaction called “bone marrow suppression”. This means that the body’s immune system is less able to fight infection and patients are at risk of sepsis.
Previous studies have identified mutations in a gene known as TPMT, which predisposes patients to thiopurine-induced bone marrow suppression. Clinicians either adjust the dose or avoid thiopurines altogether if routine tests show that patients are likely to carry faulty versions of the TPMT gene. However, only a quarter of patients who suffer from bone-marrow suppression have abnormalities in TPMT, suggesting that other genes may be involved.
Through the National Institute of Health Research Clinical Research Network, 82 NHS hospitals in the UK recruited patients to the study. In addition patients were recruited from international collaborators in the Netherlands, USA, Australia, France, New Zealand, South Africa, Malta, Denmark, Sweden, Italy and Canada. The Exeter IBD Research Group also recruited UK patients via the Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Scheme, which collects reports of patients who have experienced complications of treatment.
DNA from approximately 500 patients with IBD that suffered thiopurine-induced bone marrow suppression and 680 controls (IBD patients who had received thiopurines and had no history of bone marrow suppression), were analysed to identify genes possibly associated with this adverse drug reaction.
The researchers found an association between mutations in a gene called NUDT15 and bone marrow suppression. This gene mutation had previously only been thought important in patients of East Asian descent.
Chief Investigator of the study, Dr Tariq Ahmad, of the University of Exeter Medical School, said: “In the largest genetic analysis into the side effects of thiopurine drugs we’ve discovered variation in a gene that can help us identify who is susceptible to thiopurine-induced bone marrow suppression. In line with the NHS 10 year plan to increase personalised medicine, testing for this genetic abnormality prior to prescribing thiopurine drugs will reduce the risks to patients, and costs to the NHS, associated with this potentially serious drug side effect.

Exeter Universitywww.exeter.ac.uk/news/research/title_706404_en.html

A new way to assess the impact of normal ageing on bones, joints and muscles has been proposed that could provide a benchmark for how well older people are able to keep moving.
The composition of the body changes as we get older, as muscle strength and bone density decline. But the challenge to date has been distinguishing between the normal effects of ageing and the first signs of disease.
As a result there has been limited consensus on appropriate biomarkers of normal ageing. This has led to an unreliable picture of musculoskeletal health in older people as bone, joints and muscle have been looked at in isolation, not as a complete system.
To address this, experts at the Medical Research Council-Arthritis UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA) – a collaboration between Newcastle, Liverpool and Sheffield universities – have now proposed a set of measurements that can be used as a toolkit to assess bone, joint and muscle health.
The CIMA team say that the new toolkit will provide a consistent and holistic way to measure the gradual loss of function that everyone experiences as we get older.
In particular, they recommend the use of two biomarkers to assess bone condition – PINP and CTX, both well-established indicators of bone turnover. High levels of these biomarkers are often associated with greater fracture risk and faster rates of bone loss, particularly in older women.
The toolkit also proposes reliable indicators of cartilage damage, muscle mass, body composition and assessment of functional capability.
Professor John Mathers, from Newcastle University’s Institute for Ageing, said: “We know that when older people have limited mobility or stop being active altogether it can have a significant, negative impact on their cardio-vascular health, their neurological health and their quality of life overall, increasing the risk of disease.
“This new toolkit will help us better understand how well the whole musculoskeletal system functions as we age so that we can help people stay physically active and healthy for longer.”
The toolkit is a first step towards a comprehensive framework that could be used by researchers and clinicians – both with individuals as needed and, potentially, as part of a public health screening programme for older people.
Over time, this could identify parameters for normal musculoskeletal ageing according to gender and age. To aid this, the CIMA team say that the toolkit could be used earlier – when people are in their 50s and early 60s, before age-related disease or disability can occur – in order to get a better picture of how the musculoskeletal system ages.

Newcastle University
www.ncl.ac.uk/press/articles/latest/2018/09/toolkittoassessmusculoskeletalhealth/

DNA mutations driving cancer development are caused by different mechanisms, each of them leaving behind specific patterns, or “scars” in the genome. Using CRISPR-Cas9 technology, researchers at CeMM and the Wellcome Trust Sanger Institute at Cambridge, UK were able to show for the first time in cell culture that specific genetic alterations indeed lead to the predicted pattern of mutational signatures observed in human cancers.
When a cell develops into a tumour, something has gone terribly wrong: the uncontrolled growth, invasion of nearby tissues and finally metastasis are the result of many consecutive DNA mutations. Such an accumulation of demolished genetic material often derives from initial environmental exposures, enzymatic activities or defects in DNA replication or DNA repair mechanisms. Each of those initial mutagenic conditions creates their own pattern of DNA damage called mutational signature. Deciphering them could theoretically allow us to trace back the initial cause of a tumour, profile its properties and help find a therapeutic strategy.
However, reading those mutational signatures in tumour samples is a difficult task, as the large amount of mutations that a patient acquires during its lifetime create a noisy and uncontrolled system – even the best clinical data will, at most, provide only associations. Therefore, the group of Joanna Loizou, Principal Investigator at CeMM in collaboration with researchers from the Wellcome Trust Sanger Institute, developed an experimental setup to validate the concept of mutational signatures in cell culture.
The findings of this study not only confirm an analytical principle that describes mutational processes and cancer development, mutational signatures are a direct mechanistic read-out of specific dysfunctions of a cell. Thus, even if the underlying gene defect is unknown, mutational signatures could be used as biomarkers for the molecular characterization of tumors – a new diagnostic tool to improve the precise and personalized treatment of cancer.

CeMM
cemm.at/news/

The largest genetic study of its kind ever to use accelerometer data to examine how we slumber has uncovered a number of parts of our genetic code that could be responsible for causing poor sleep quality and duration.
The international collaboration, led by the University of Exeter, has found 47 links between our genetic code and the quality, quantity and timing of how we sleep. They include ten new genetic links with sleep duration and 26 with sleep quality.
The Medical Research Council-funded study looked at data from 85,670 participants of UK Biobank and 5,819 individuals from three other studies, who wore accelerometers – wrist-worn devices (similar to a Fitbit) which record activity levels continuously. They wore the accelerometers continuously for seven days, giving more detailed sleep data than previous studies, which have relied on people accurately reporting their own sleep habits.
Among the genomic regions uncovered is a gene called PDE11A. The research team discovered than an uncommon variant of this gene affects not only how long you sleep but your quality of sleep too. The gene has previously been identified as a possible drug target for treatment of people with neuropsychiatric disorders associated with mood stability and social behaviours.
The study also found that among people with the same hip circumference, a higher waist circumference resulted in less time sleeping, although the effect was very small – around 4 seconds less sleep per 1cm waist increase in someone with the average hip circumference of around 100cm.
The team involved colleagues from the Center for Sleep and Circadian Neurobiology in Pennsylvania, Massachusetts General Hospital as well as the Netherlands, France and Switzerland. They found that collectively, the genetic regions linked to sleep quality are also linked to the production of serotonin – a neurotransmitter associated with feelings of happiness and wellbeing. Serotonin is known to play a key role in sleep cycles and is theorised to help promote deeper and more restful sleep.
Senior author Dr Andrew Wood, of the University of Exeter Medical School, said: “We know that getting enough sleep improves our health and wellbeing, yet we still know relatively little about the mechanisms in our bodies that influence how we sleep. Changes in sleep quality, quantity and timing are strongly associated with several human diseases such as diabetes and obesity, and psychiatric disorders.
The group also found further evidence that Restless Leg Syndrome is linked to poorer sleep from the genetic variants they found to be associated with sleep measures derived from the accelerometer data.
University of Exeter https://www.exeter.ac.uk/news/research/title_711082_en.html

• Experts highlight that Middle Eastern populations are underrepresented in disease research
• UAE Vision 2021 aims to reduce cancer-related deaths, which WHO estimated to be 25.6 deaths per 100,000 population in the UAE in 2017
• Barriers to providing precision medicine in the Arab world to be discussed at MEDLAB Congress taking place from 4 – 7 February 2019 in Dubai

Dubai, United Arab Emirates, 12th December 2018: Ahead of the upcoming MEDLAB Exhibition & Congress, the MENA region’s largest medical laboratory event, experts are highlighting the need for advancing genetic and disease research in the Arab world in order to provide targeted gene therapies for certain cancers for citizens in the UAE.

This is in line with the UAE Vision 2021 National Agenda, which aims to reduce cancer-related deaths in the country, with the World Health Organisation (WHO) estimating 25.6 deaths per 100,000 population in the UAE in 2017. To achieve this aim, the UAE government regularly launches national awareness and preventative campaigns within the framework of ‘Itmenan’ which involves the ‘Universal Periodic Examination’ and ‘Early Detection of Cancer’ initiatives adopted by the Council of Ministers.

Targeted therapies, or precision medicine, is defined as tailoring of medical treatment to the individual characteristics of each patient. It is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. For example, for cancer treatments, based on genetic testing, a physician can choose the most effective chemotherapy based on the mutation or biomarker identified.

According to the WHO, while 70% of deaths from cancer occur in low and middle-income countries, only one in five low and middle-income countries have the necessary data to drive cancer policy. More than 90% of high-income countries reported available treatment services compared to less than 30% in low-income countries. While a portion of countries in MENA do have a high GDP, they are still considered developing economies according to the United Nations.

Commenting, Dr Sara Sorrell, Consultant Family Medicine, Intercare Health Center, Abu Dhabi, UAE, said: “It is well recognised that Middle Eastern populations are underrepresented in disease research and, to date, there is no research to indicate the impact of precision medicine in the UAE. But I think that this is still premature as we don’t even have enough data on the general population genetics of this part of the world, so this is really the first step. 

“For instance, if a different mutation is found to cause a particular cancer here, compared to European descent populations, this may present a novel target for new cancer therapies for local populations. Or, if a new drug comes on the market, what’s the effect in the local population? Therefore, advancing genetic and disease research in the UAE and the Arab world is very important. For this to occur, there needs to be both a focus on funding research as well as formulating policies around research and healthcare innovation to protect patients, scientists, and physicians,” she added.

Molecular diagnostics and genetics experts from the MENA region will gather at the upcoming MEDLAB Congress taking place from 4 – 7 February 2019 at Dubai World Trade Centre to discuss topics such as barriers to providing precision medicine in the Arab World, strategies for the prevention of genetic diseases, and Next-Generation Sequencing in oncology, among others.

Commenting on the importance of scientific exchange in the regional medical laboratory industry, Rejoy Penacerrada, Conference Director, MEDLAB Congress, said: “The conferences provide an important platform for the region’s medical laboratory community to engage in discussion that will promote the role of genetic and population research in advancing the health of citizens across the region. This is led by the intense interest in precision medicine, with the region’s laboratories now actively expanding their test menus for more personalised diagnostic services.”

Organised by Informa Exhibitions, the MEDLAB Congress brings together more than 6,700 conference delegates to hear from more than 110 speakers from 20 countries in an effort to provide advanced medical laboratory techniques for better health.

For a closer look at MEDLAB 2019, please visit www.medlabme.com