Researchers at the University of Southampton are investigating the genes that are responsible for Inflammatory Bowel Disease (IBD) in children, with the aim of personalising treatments for individual patients.
Complex diseases such as IBD, asthma, heart disease and Alzheimer’s disease are not caused by a mutation of just one gene, but by mutations of multiple genes in our genetic code. In order to help patients with IBD, a team of researchers in the Genomic Informatics Group at the University, are looking at the genetic code of individual children that suffer from IBD to build up a profile of which genes cause the disease.
Debilitating disease
IBD is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn’s disease, which affects any part of the gastrointestinal tract from the mouth to the anus, and ulcerative colitis, a condition that affects the lining of the colon. However, there are many different sub-categories of these two types of the disease, making it difficult to treat individual patients effectively.
In addition, there are a significant number of patients under 18 years of age that are diagnosed with IBD and even toddlers can suffer from the disease. “It is a hugely debilitating disease and is almost an order of magnitude more severe in tiny children, because they are at an age when they need to take on nutrition in order to grow,” says Dr Sarah Ennis, Head of the Genomic Informatics Group. “As the disease begins in childhood, we suspect that environment has less of a role to play than genetics, so this is a good hunting ground for us to look for genes specific to IBD,” she adds.
Sarah explains that human genomics is the study of the complete genome and involves determining the entire DNA sequence and mapping genetic code. A genome encodes all of an organism’s hereditary information and can hold the key to the diseases that any individual could be susceptible to. “In 2003 it took about $10bn, multiple groups around the world and 10 years of research to get one reference human genome,” says Sarah She explains how far we have now come: “Now I can spend between £400 and £700 to get the genetic sequence for all of a patients’ exomes – the regions of the genome that code for proteins and are most likely to contain mutations with disease impact.”
DNA sequencing
Housed in University Hospital Southampton is the regional referral centre for children diagnosed with IBD. Sarah’s team started working with clinical colleagues in October 2010 to recruit eight children to their study looking at the genetics of paediatric IBD, but now they have about 160 patients. The team are using Next Generation Sequencing (NGS) technology to create individual profiles of genetic changes across a panel of genes known to influence IBD risk.
Blood is taken from the patient and the DNA is extracted. The team then send the DNA for sequencing which involves the use of molecular techniques to target the sections that code for proteins. The extracted sections are then broken up into smaller parts that contain only about 150 base pairs of DNA. “These are put through the sequencer, and multiple reads of these sections identify the exome of a gene,” says Sarah. “For each patient we have produced a profile of their individual variation across the genes that are known to influence IBD risk. We have found that despite having common diagnoses, each individual presents with a unique profile of genetic variants,” says Sarah.
The complete picture
The University hosts the only National Institute for Health Research (NIHR) funded biomedical research centre for nutrition in the country, which means that as well as characterising the patients’ clinical progression and obtaining their DNA for analysis, Sarah and her team can characterize the nutritional status of each patient as well as assessing how each patient responds to certain drugs. “We also get the parents’ DNA and the DNA of any other family members that may suffer from the disease,” she says.
The team is also working with the University of Aberdeen to look at the microbiome data – the bacteria in each child’s gut – to see if there are any similarities between patients. The team will therefore have all the data on each patient’s expressed genes, all their surgical, clinical and nutritional information as well as information on the bacteria present in their guts. “We plan to get this data at the time of diagnosis, time of remission, and time of relapse. So we are trying build up the complete picture and history for each individual,” says Sarah.
Personalised medicine
The amount of data that the team is collecting on each patient can use up gigabytes of memory. To help analyse the information, the team is using Iridis 3, Southampton’s supercomputer, in order to produce one computer file for each individual containing all the variants that are different from the reference human genome.
“We can then use these data to look at which genes in the particular patient cause the disease,” Sarah tells New Boundaries. “By identifying the specific sub-sets of genes that cause the disease on a case-by-case basis we may be able to target drugs to the individual thereby personalising their clinical treatment.”
As new drugs and therapies emerge, knowing which specific biological pathways are impaired on a case-by-case basis will lead to targeted treatments tailored to individual patients. The team plan to build on this work to identify which specific and detailed clinical characteristics are shared by patients with similar genomic profiles. “Ultimately, this may help us give much more specific diagnoses to individuals rather than the ‘umbrella terms’ that are currently used and this in turn will help inform clinicians of the best treatments for their patients,” says Sarah.
Future plans
“At some stage in the future, it will be possible to take a patient’s blood sample and with that predict the genetic pathways that are sub-optimal or functioning very poorly, the types of bacteria in the gut and personalise the treatment to keep the disease at bay,” says Sarah.
The team expect that their findings will translate into adult medicine as well as aiding screening in relatives of those affected by this familial disease. “We are not trying to just find one more gene that might be involved in IBD, we are looking at individual patients, building up profiles of all the sub-optimal genes in order to understand the variety of genes involved.”
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- Genomic Informatics Group
- University Hospital Southampton
- National Institute for Health Research (NIHR)
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