Genetic susceptibility to ulcerative colitis

Behind the Headlines

Monday October 6 2008

Coloured barium X-ray of the colon of a 60 year old man with ulcerative colitis

Researchers have found an association between the inflammatory bowel condition ulcerative colitis and the “gene that encodes for interleukin 10 (IL10) – a compound which regulates inflammation”, BBC News website reports. Ulcerative colitis affects around 100,000 people in the UK, and symptoms include bloody diarrhoea, abdominal pain, losing weight and needing to go to the toilet frequently. The website reports that “the administration of interleukin 10 to individuals with colitis has been reported to have a positive effect in initial studies, although this potential therapy has not been assessed more thoroughly”.

This study points researchers towards areas of the genome that warrant further study in people with ulcerative colitis, although the variant(s) that actually causes this increase has not yet been identified. However, further studies will be needed to investigate whether IL10 treatment would be helpful for people with ulcerative colitis.

Where did the story come from?

Dr Andre Franke from Christian–Albrechts University in Germany, and colleagues from other universities in Europe, carried out this research. The study was funded by the German Ministry of Education and Research (BMBF). It was an advance online publication in the peer-reviewed scientific journal, Nature Genetics.

What kind of scientific study was this?

This was a genetic case-control study called a genome-wide analysis. The researchers were looking for particular genetic variations that were associated with the susceptibility to developing a form of inflammatory bowel disease called ulcerative colitis. This disease is estimated to affect between 21 and 246 people per 100,000 of the population in North America and Europe. It is known that genetics plays a role in developing ulcerative colitis, as siblings of people with the disease are six to nine times more likely to develop this disease than the general population.

The researchers identified 1,167 people with ulcerative colitis (cases) and 777 people who did not have the condition (controls). They obtained DNA samples for all of the cases and controls, and looked at 440,794 specific points across the DNA, called SNPs, where single “letters” of the genetic sequence are known to vary. They then compared the sequences to see if there were any SNPs where a particular “letter” was more common in the cases than in the controls. If a particular “letter” or variant is more common among cases than controls, this variant is said to be “associated” with the disease.

To confirm their findings, the researchers repeated their test on DNA from an additional 1,855 cases with ulcerative colitis and 3,091 healthy controls from three other European studies. Researchers carrying out these tests were blinded to whether the DNA came from a person with ulcerative colitis or not. Only those variants that showed association with the disease in both tests were included. The researchers went on to look at which genes lay close to these associated variants, as they may be involved in the development of the disease.

What were the results of the study?

In their first analysis of 1,944 people with or without ulcerative colitis (cases and controls), the researchers identified a number of variants that were significantly more common in people who had ulcerative colitis (cases). They took the 20 variants showing the strongest association with the disease, and tested these in three additional sets of cases and controls (replication samples).

Five of these variants showed a strong association with the disease across all three replication samples. Three of these variants lay near to a complex (group) of HLA genes (genes involved in the immune system) on chromosome 6, while one variant was near to the IL10 gene on chromosome 1; another one was near to the ARP2C region on chromosome 2. These susceptibility variants were estimated to be associated with between 9.8% and 47.8% of the risk of developing ulcerative colitis.

"Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the ulcerative colitis subtype of inflammatory bowel disease."

Andre Franke, lead author

The researchers went on to look at the variant near to IL10 in more detail, as this gene produces a protein which has a suppressive effect on the immune system and has previously been thought to play a role in inflammatory bowel disease, such as ulcerative colitis. When the original and replication samples were pooled, this variant was associated with an increase of 35% in the odds of developing ulcerative colitis. The researchers looked at 22 more variants in and around IL10 in cases and controls, and found that a number of these variants also showed association with ulcerative colitis. Their findings suggested that there might be more than one variation in this region contributing to the increase in risk of ulcerative colitis.

The researchers also determined the sequence of the entire IL10 gene in 94 people with ulcerative colitis, 94 people with Crohn’s disease (another form of inflammatory bowl disease) and 94 healthy controls. Although they found a number of variations in the sequence of the gene, they did not identify a single variation that was clearly responsible for causing an increased risk of developing the condition.

What interpretations did the researchers draw from these results?

The researchers concluded that their findings suggested that a defect in IL10 function is key to the development of ulcerative colitis. They suggest that IL10 “should be worthy of consideration in clinical trials in [ulcerative colitis]”.

What does the NHS Knowledge Service make of this study?

This study provides evidence that variations within the region of the IL10 gene are contributing to the risk of developing ulcerative colitis, although the variant(s) that actually causes this increase has not yet been identified. The findings were replicated in more than one group of people, and this increases the confidence in these results. As the authors suggest, further studies will be needed to investigate whether IL10 treatment would be helpful for people with ulcerative colitis. The previous use of this agent in human studies may make it easier for these trials to start, but it will still be a number of years until the results of such trials will be available. It is not known yet whether this treatment provides benefits to people with ulcerative colitis.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Inflammatory bowel gene uncovered. BBC News, October 5 2008

Links to the science

Franke A, BalschunT, Karlsen TH, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 2008; Oct 5 [Epub ahead of print]

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