Skip to content

Gut reaction – Investigating coeliac disease

7 Apr, 2009

Professor David van Heel is at the cutting edge of research into coeliac disease, a common and debilitating condition with no cure. Chrissie Giles spoke to him and other leading figures in the field to find out what we know about the causes and treatment of this disease.

It can prevent you from joining the armed forces, it makes eating many everyday foodstuffs impossible and it is surprisingly common. Coeliac disease is a much misunderstood disorder, which, often mistaken for a food allergy, is actually an autoimmune disease caused by intolerance to gluten – the major protein in wheat. It has no cure.

Some decades ago, coeliac disease was thought of as an illness of children, causing failure to thrive. Now, doctors are finding the disease in adults more than in children (currently, there are nine adults for every child diagnosed). Coeliac disease is thought to affect 1 in 100 people in the UK, yet studies suggest only 1 in 8 affected has been diagnosed. This, in part, could be because the symptoms can vary from very mild to very severe.

As Professor of Gastrointestinal Genetics at Barts and The London School of Medicine and Dentistry, David van Heel sees hundreds of patients with coeliac disease every year. As well as helping these people cope with their symptoms, he and his colleagues have uncovered a raft of new genetic links to the disease, helping researchers worldwide in their own research (see ‘Making an impact’, below).

Genome-wide search

Coeliac disease is highly heritable, and the involvement of certain types of key immune system genes (so-called human leukocyte antigen or HLA genes) has been known since the 1970s. But, explains Professor van Heel, it was also clear that the HLA genes were only part of the story.

“Some 99 per cent of people with coeliac disease carry HLA gene variants called DQ2 or DQ8. These types are also common in the general population, so they are necessary to cause coeliac disease, but not sufficient.”

So, with funding from Coeliac UK and the Wellcome Trust, Professor van Heel and his team carried out the first genome-wide association study in coeliac disease, to try to find more genetic links to the disease.

Genome-wide association studies compare single nucleotide polymorphisms (SNPs; common DNA mutations that occur roughly once in 1000 bases) in people with and without particular traits or diseases, to try to find genes associated with them.

In a study published in 2007, the researchers found that coeliac disease was associated with genetic variation in two genes, which code for interleukin 2 and interleukin 21. “These interleukins control T-cell function,” says Professor van Heel. “We don’t know what the T cells are ‘doing’ in coeliac disease, but we would expect them to perhaps behave more strongly or respond more easily than in people without the disease.”

A further genome-wide association study published by the group in 2008 identified an additional seven genetic variants linked to the disease, several of which had also been implicated in rheumatoid arthritis and type 1 diabetes – other autoimmune diseases.

A recent paper by Professor van Heel and colleagues from Cambridge brought the number of non-HLA genetic regions associated with coeliac disease to 11, and those associated with type 1 diabetes to 21. Again, some genetic regions were involved in both diseases, bringing the total to seven. Interestingly, two of these ‘shared’ regions seemed to protect against diabetes, while conferring susceptibility to coeliac disease.

The researchers think that these shared genetic regions regulate the mechanisms that cause an individual’s immune system to attack the beta cells in the pancreas and the small intestine. Their results suggest that type 1 diabetes and coeliac disease not only share genetic causes but could have similar environmental triggers as well.

The Trust has recently funded a further round of genome-wide association studies, which includes research into coeliac disease. The researchers will study SNPs in more detail, and copy number variation – where chunks of DNA are gained or lost in individuals.

“At the moment we have explained around 30 to 40 per cent of the heritability of coeliac disease, but we think that there is still a load of genetic findings still out there,” says Professor van Heel.

Cereal killer

What do these advances in our understanding of the factors underlying coeliac disease tell us about how to treat it?

When a person with coeliac disease eats gluten, their immune system attacks the mucosa of the small intestine, preventing it from absorbing nutrients normally. The effects, such as severe diarrhoea and vomiting, can last for days. Contamination can come from things as seemingly minor as breadcrumbs in a toaster. Professor van Heel says that while there’s no cure for coeliac disease, there is a treatment: a gluten-free diet. Such a diet can be tricky to manage, as well as being inconvenient. “This isn’t just a treatment,” says Professor van Heel, “it’s a morbidity in its own right.”

Other treatments in development include adding substances based on bacterial enzymes to food to digest the gluten within, as well as immune-based treatments.

But it’s not as simple as finding the genes involved and designing a treatment around them, Professor van Heel explains. “If you switch off the IL2 gene then you’re at risk of lots of horrible infections. What this kind of research does do, though, is give you new insights into the pathways primarily involved in causing the disease.”

Coeliac disease is not just down to genes; findings from twin studies – and the fact that its onset is often in a person’s 30s or 40s – suggest that environmental factors are also involved. Researchers are trying to discover what these are and how they interact with genetics.

Other fascinating avenues that require investigation include whether breastfeeding is protective against coeliac disease when babies are weaned on to gluten-containing foods, and whether certain viral infections in infancy can predispose to the disease.

“There are some studies that have shown that, in a few children, coeliac disease seems to go away spontaneously,” says Professor van Heel. “It appears that, in these patients, the immune system can be tipped back to tolerance. Whether we can do this clinically I don’t know, but it’s certainly an interesting question.”

  • For more information about coeliac disease, see Coeliac UK.

Further information

“I went out for lunch and ended up in A&E”

Sue Harte, 57, from Devon, was diagnosed with coeliac disease around 18 months ago.

“I’d had the symptoms of coeliac disease since the age of 40, when I suffered severe diarrhoea for six weeks and subsequently lost 2 stone in weight. Despite this and further episodes, the symptoms were misdiagnosed several times, including as irritable bowel syndrome and stress. It was only when I moved house and found a new doctor that I was diagnosed.

“I feel so much better now that I’m on a gluten-free diet, and suffer symptoms only if I eat food that has been cross-contaminated. I had a carvery meal and ended up in A&E with severe vomiting and diarrhoea, because the serving spoons for the leeks (served in a sauce containing flour) and plain vegetables had been swapped.

“I miss the freedom of being able to eat whatever I want, or spontaneously deciding to go out for a meal or pick up a takeaway, but feeling better far outweighs these disadvantages.

“Some people think a gluten-free diet is a bit of a fad or conscious choice, but it’s more than that. It might not be life-threatening like a peanut allergy, but for coeliacs eating gluten can really make you ill and have other health implications. After years of misdiagnosis I have early osteoporosis, caused by malabsorption of nutrients, particularly calcium.

“I get some gluten-free foods on prescription, but I’m surprised there’s not more available to buy, at a reasonable price.”

Making an impact

What have the short-term effects of Professor van Heel’s research been? We asked two of the world’s leading researchers working on coeliac disease for their thoughts.

Professor Ludvig SollidProfessor Ludvig Sollid is Director of the Centre for Immune Regulation at the University of Oslo and the Rikshospitalet University Hospital, Norway.

“Professor van Heel’s work has definitely had a big impact on the field. Since the discovery of HLA-DQ2, studies into the genetics of coeliac disease have more or less led nowhere – until his genome-wide association study. We are experiencing a revolution in the field of coeliac disease, similar to that being seen in many other multi-gene disorders.

“The susceptibility genes identified by Professor van Heel provide a roadmap for further investigation, and my group is particularly interested in finding out what these genes might be doing.

“What’s been disappointing is that the effects of the novel genes in terms of genetic risk are small. There are some 11 genes associated with coeliac disease, excluding HLA-DQ2, but a huge number are needed to fill the gap – perhaps hundreds – we just don’t know yet.”

Dr Bob AndersonDr Bob Anderson is a Lab Head at the Autoimmunity and Transplantation Division at the Walter and Eliza Hall Institute, Parkville, Australia.

“The funding available for research into coeliac disease has always been limited, and the main challenge for researchers in the field has been to secure research support. An effect of Professor van Heel’s genetics studies has been to save considerable resources by ending the small-scale genetics research that had many false starts and produced findings that have not been replicable.

“The genes implicated by Professor van Heel’s work emphasise the other components of the immune system that influence T-cell behaviour. In the longer term, knowledge of these genes may guide the therapy prescribed for patients. Coeliac disease has become a wonderful testing ground to understand the biology of, and to develop therapeutics for, chronic immune diseases such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis.”

This article appeared in ‘Wellcome News’ 58.

No comments yet

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: