Crohn’s disease risk and prognosis determined by different genes, study finds
Researchers have identified a series of genetic variants that affect the severity of Crohn’s disease, an inflammatory bowel disease – but surprisingly, none of these variants appear to be related to an individual’s risk of developing the condition in the first place
Crohn’s disease is one of a number of chronic ‘complex’ diseases for which there is no single gene that causes the disease. In fact, to date around 170 common genetic variants have been identified that each increase the risk of an individual developing the disease. The conventional wisdom has been that there exists a ‘tipping point’: if someone has enough of these genes, they become very likely to develop the disease – and the more of the variants they carry, the more the severe the disease will then be.
However, in a study published today in Nature Genetics, a team of researchers led by the University of Cambridge has shown that this is not the case: genetic variants that affect the progression, or prognosis, of a disease operate independently of those that increase the likelihood of developing the disease in the first place.
“Genetic studies have been very successful at identifying genetic risk factors for Crohn’s disease, but have told us virtually nothing about why one person will get only mild disease while someone else might need surgery to treat their condition,” says Dr James Lee from the Department of Medicine at Cambridge. “We do know, though, that family members who have the disease often tend to see it progress in a similar way. This suggested to us that genetics was likely to be involved in prognosis.”
The researchers looked at the genomes – the entire genetic makeup – of more than 2,700 individuals, who were selected because they had either had experienced particularly mild or particularly aggressive Crohn’s disease. By comparing these patients’ DNA, the researchers found four genetic variants that influenced the severity of a patient’s condition. Strikingly, none of these genes have been shown to affect the risk of developing the disease.
The team then looked at all the known genetic risk variants for Crohn’s and found that none of these influenced the severity of disease. “This shows us that the genetic architecture of disease outcome is very different to that of disease risk,” adds Professor Ken Smith, Head of the Department of Medicine. “In other words, the biological pathways driving disease progression may be very different to those that initiate the disease itself. This was quite unexpected. Past work has focussed on discovering genes underlying disease initiation, and our work suggests these may no longer be relevant by the time a patient sees the doctor. We may have to consider directing new therapies to quite different pathways in order to treat established disease”
One of the genetic variants discovered by the team was in a gene called FOXO3. This gene is involved in modulating the release of the cytokine TNFα – cytokines are proteins released into the blood by immune cells in response to infection or, in the case of conditions such as Crohn’s, to the body erroneously attacking itself. This FOXO3-TNFα pathway is also known to affect the severity of rheumatoid arthritis, another auto-inflammatory disease.
Another of the variants was close to the gene IGFBP1, which is known to play a role in the immune system. This genetic region, too, has previously been linked to rheumatoid arthritis, in a study looking at the presence of a particular antibody in patients – presence of this antibody is associated with more severe disease.
The third genetic variant was in the MHC region, which is responsible for determining how our immune cells respond to invading organisms. This region has been implicated in a number of auto-immune diseases, including Crohn’s, but the genetic variant that alters Crohn’s disease risk is different to the one that affects prognosis. The variant the team identified, which was associated with a milder course of Crohn’s disease, was shown to affect multiple genes in this region, and result in a state that is known to cause weaker immune responses.
The final variant occurred in the gene XACT, about which very little is known; however, in adults this gene appears to be mainly active in cells in the intestine – the organ affected by Crohn’s disease. “This discovery has shown us a new way of looking at disease and opens up potential new treatment options, which could substantially ease the burden of Crohn’s disease,” says Dr Lee. “What’s more, we have evidence that some of these prognosis genes will be shared with other diseases, and as such this approach could be used to improve treatment in a number of conditions.”
The study has been welcomed by Crohn’s and Colitis UK, who helped fund the study. “This is an exciting breakthrough which offers new hope for people who suffer every day from Crohn’s and Colitis,” says Dr Wendy Edwards, Research Manager at Crohn’s and Colitis UK. “The research sheds new light on why some people with inflammatory bowel disease experience more severe symptoms than others, which has been little understood until now.”
As well as its implications for Crohn’s and other diseases, the approach taken by the researchers has suggested that there is value in re-examining previous genetic studies. Around a third of the genomes of Crohn’s disease patients analysed in this study had been collected for a previous study in 2007. By dividing the patients into groups categorised by disease severity, the researchers were able ask new questions – and gain new insights – from the old data.
The research was mainly funded by NIHR Cambridge Biomedical Research Centre, Crohn’s and Colitis UK and the Evelyn Trust.
Written by the University of Cambridge
NIHR research award for Gillian Gatiss, Addenbrooke’s liver transplant dietitian
Gillian Gatiss, a dietitian in the Addenbrooke’s team that works with patients awaiting liver transplantation, has been awarded the HEE/NIHR Clinical Doctoral Research Fellowship through the ICA HEE/NIHR Integrated Clinical Academic Programme for non-medical healthcare professions. She is set to advance knowledge through her PhD at the University of Cambridge about how the nutritional status of patients with liver cirrhosis can be improved, focusing on developing an individualised approach to their nutritional treatment.
For patients with liver disease, eating an appropriate diet is anything but straightforward. Up to 60,000 people in England and Wales have cirrhosis and numbers are rising fast. As the disease progresses, patients often experience muscle-wasting combined with either increased or decreased fat stores.
Gillian explained: “My specific job as a dietitian is to assess patients presenting for liver transplantation. I check that they are nutritionally fit and if not, we put a plan in place to improve their nutritional status before transplantation. Patients are so variable. We need better ways to help each person meet their energy requirements, eat the right food and stay as strong as possible. For example, we measure weight but the liver cirrhosis means that people are often retaining a lot of fluid and this obviously means the weight measurements can be misleading. The research award means I’ll be able to look at completely new ways to assess and respond to people’s individual needs”.
In 2011, Gillian undertook the Masters in Clinical Research, supported by NIHR through what’s now called the ICA programme. She said: “I wanted to be able to do research in practice. I was questioning how we could improve things. With the liver patients, rather than a one size fits all approach, we are looking to tailor what we do for our patients”.
Support from the Addenbrooke’s Charitable Trust (ACT) and the NIHR Cambridge Biomedical Research Centre (BRC) was key to Gillian’s success, enabling her to develop her 2016 NIHR proposal.
The ACT/BRC Fellowship gave me the time and support I needed to develop a competitive doctoral application and it meant I could continue on a clinical/academic pathway – Gillian Gatiss
Gillian said: “After the Masters, I went back to working clinically with patients but was keen to apply for research grants. I realised the next step was to work on a PhD. But I needed support to put the HEE/NIHR Doctoral Research Fellowship application together – to review the literature, discuss the research with supervisors, develop the research protocol, consult with patients and the public, determine the training programme and finances – and I was so lucky to be one of the first recipients of the ACT/BRC internal research Fellowships. The ACT/BRC Fellowships, which are now in their third year, are intended to provide time and support for nurses, midwives and AHPs to develop competitive doctoral applications. That Fellowship enabled me to work on the NIHR proposal three days a week for six months and without it I would never have managed to pull it all together. It meant I could continue on a clinical/academic pathway. I didn’t want to leave patients behind. I wanted to carry on treating them”.
Gillian’s research will be in three parts. She explained that the first step is to rethink how patients’ energy requirements are worked out: “Dietitians use predictive equations to calculate people’s energy requirements but these simple calculations were originally designed for use across populations and not for individuals. So for this project we’ll test a new portable calorimeter – an energy calculating machine – to determine if it can give us much more precise results for each individual patient. One patient who is on our steering group said: ‘it would be fantastic to know my actual requirements”.
“The next step is to consider how appetite works in people with liver disease. We don’t know very much about how liver disease affects gut hormones, some of which stimulate appetite and some of which suppress it. But we do know that people with liver cirrhosis often have a poor appetite and they might feel full very quickly. So we’ll look at satiety after eating and levels of gut hormones in two groups – one healthy group and another group of people with liver cirrhosis – and we hope that any variations between the two groups may indicate treatments to boost appetite”.
“The final strand of our work will be to ask patients about their experiences with diet during their illness and we hope that something that we have never thought of might come up, which could be used to improve patients’ outcomes”.
I am just so delighted to see Gillian take this forward with the HEE/NIHR Fellowship. These are nationally very competitive awards, and I want to thank the ACT and BRC for funding the internal research Fellowships that provided the time and support she needed to be successful – Professor Christi Deaton
Professor Christi Deaton, Florence Nightingale Foundation Professor of Clinical Nursing Research, said: “This research has the potential to improve nutritional assessment and management, and hopefully the outcomes of people with liver cirrhosis. It will have implications for other patient groups as well. I am just so delighted to see Gillian take this forward with the HEE/NIHR Fellowship. These are nationally very competitive awards, and I want to thank the ACT and BRC for funding the internal research Fellowships that provided the time and support she needed to be successful”.
Find out more
The next round for the BRC/ACT internal research fellowships will be held in Autumn 2017. Please contact firstname.lastname@example.org to find out more.
About Professor Christi Deaton
Funding announcement for our CRF
On Friday 18th November, the Department of Health announced a further £112 million investment into NIHR Clinical Research Facilities (CRFs) across the country.
Following a competitive application and assessment process, funding has been awarded to 23 NHS organisations. Provided over the next five years, the funding will pay for specialist research nurses and technical staff, as well as providing cutting-edge facilities to support clinical research and trials.
We can announce our NIHR/Wellcome Trust Cambridge Clinical Research Facility have had an uplift of a 6% increase in funding to £11.45 million commencing in 2017. Caroline Saunders, Director of Operations said: “We’re delighted with the funding we’ve been awarded to enable us to staff our expanding CRF, which will include four new research facilities due to open in the spring of 2017. This is excellent news for patients and healthy volunteers taking part in research and for our investigators.”
Minister for Public Health and Innovation Nicola Blackwood said: “UK researchers lead the world and our investment in this area so far has led to a variety of breakthroughs, including the first new asthma treatment in a decade, and a promising treatment for peanut allergies in children, to name just two.
“We know that such ground breaking research simply would not happen without the support of these Clinical Research Facilities. I’m delighted to announce this £112 million of extra funding to support the skilled personnel and cutting-edge facilities we need to keep the UK at the forefront of clinical research.”
Cocaine addiction leads to build-up of iron in brain
Cocaine addiction may affect how the body processes iron, leading to a build-up of the mineral in the brain, according to new research from the University of Cambridge. The study, published today in Translational Psychiatry, raises hopes that there may be a biomarker – a biological measure of addiction – that could be used as a target for future treatments.
Cocaine is one of the most widely-used illicit drugs in the Western world and is highly addictive. A report last year by the UK government’s Advisory Council on the Misuse of Drugs found that almost one in 10 of all 16-to 59-year-olds have used cocaine in their lifetime. Cocaine use was implicated in, but not necessarily the cause of 234 deaths in Scotland, England and Wales in 2013. However, despite significant advances in our understanding of the biology of addiction – including how the brains of people addicted to cocaine may differ in structure – there is currently no medical treatment for cocaine addiction; most individuals are treated with talking or cognitive therapies.
A team of researchers led by Dr Karen Ersche from the Department of Psychiatry at Cambridge examined brain tissue in 44 people who were addicted to cocaine and 44 healthy control volunteers. In the cocaine group, they detected excessive amounts of iron in a region of the brain known as the globus pallidus, which ordinarily acts as a ‘brake’ for inhibiting behaviour.
Particularly striking was the fact that the concentration of iron in this area was directly linked with the duration of cocaine use – in other words, the longer that participants had used cocaine, the greater the accumulation of iron. At the same time, the increased iron concentration in the brain was accompanied by mild iron deficiency in the rest of the body, suggesting that iron regulation in general is disrupted in people with cocaine addiction.
“Given the important role that iron plays in both health and disease, iron metabolism is normally tightly regulated,” explains Dr Karen Ersche from the Department of Psychiatry. “Long-term cocaine use, however, seems to disrupt this regulation, which may cause significant harm.
“Iron is used to produce red blood cells, which help store and carry oxygen in the blood. So, iron deficiency in the blood means that organs and tissues may not get as much oxygen as they need. On the other hand, we know that excessive iron in the brain is associated with cell death, which is what we frequently see in neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease.”
The Cambridge researchers now aim to identify the precise mechanisms by which cocaine interacts with iron regulation. Dr Ersche believes the most likely mechanism is that cocaine disrupts iron metabolism, possibly by reducing the absorption of iron from food, increasing the permeability of the blood-brain-barrier so that more iron enters the brain, where it can accumulate.
Although excess iron in the brain is associated with neurodegeneration, there is no suggestion that cocaine addiction leads to an increased risk of Alzheimer’s or Parkinson’s disease. The mechanism underlying the increase in iron in the brain in Parkinson’s disease, for example, is different to that in cocaine addiction, as are the affected brain regions.
As an essential micronutrient, iron can only be obtained through our diet and cannot be excreted, other than through blood loss. The researchers now want to find out whether means of correcting the disruptions in iron metabolism might slow down or even reverse the accumulation of iron in the brain, and ultimately help affected individuals to successfully recover from cocaine addiction.
This work was funded by the Medical Research Council and was conducted at the NIHR Cambridge Biomedical Research Centre and the Behavioural and Clinical Neuroscience Institute.
Written by the Unviersity of Cambridge