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

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