Genetic Variants Driving Crohn's Disease Progression Differs From Disease Risk

Different genetic variants determine the risk and prognosis of Crohn’s disease.

To date, approximately 170 common genetic variants have been identified that each increase the risk of developing Crohn’s disease. It is commonly believed a tipping point exists; if an individual has enough of these genes they will most likely develop the disease. The more variants they carry, the more severe the disease will be.

But in a new study published in Nature Genetics, a team of investigators found that genetic variants that affect the prognosis of the disease work independently of those that increase the likelihood of developing the disease to begin with.

“Genetic studies have been very successful at identifying genetic risk factors for Crohn’s disease, but have told us virtually nothing about why 1 person will get only mild disease while someone else might need surgery to treat their condition,” said investigator Dr James Lee. “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.”

For the study, the investigators examined genomes of more than 2700 individuals with mild or aggressive Crohn’s disease. After comparing the patients’ DNA, the results of the study showed that 4 genetic variants influenced the severity of a patient’s condition. Interestingly, none of these 4 genes have been shown to affect the risk of developing the disease.

The investigators examined all of the known genetic risk variants for Crohn’s, and found that none of them influenced disease severity, according to the study.

“This shows us that the genetic architecture of disease outcome is very different to that of disease risk,” said investigator Ken Smith. “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 focused on discovering genes underlying disease initiation, and our work suggest 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 genetic variant discovered by investigators was in the gene FOXO3, which is involved in modulating the release of cytokine TNF. The FOXO3-TNF pathway is also known to affect the severity of rheumatoid arthritis, and other autoinflammatory diseases.

A variant close to the gene IFGBP1—–known to play a role in the immune system––was also identified. This genetic region was previously linked to rheumatoid arthritis during a study that showed the antibodies’ presence was associated with more severe disease.

The third genetic variant uncovered was found in the MHC region, which is responsible for determining how the immune cells respond to foreign organisms, according to the study. Although this region has been implicated in several autoimmune diseases, in Crohn’s, the genetic variant that alters the disease risk differs from the variant that affects prognosis.

The variant the investigators identified was associated with a milder state of Crohn’s disease, and was shown to affect multiple genes in this region, resulting in a state that causes weaker immune responses.

The last variant occurred in the gene XACT, about which very little is known, according to the study. However, in adults the gene appears to be mainly active in cells located in the intestine.

“This discovery has shown us a new way of looking at the disease and opens up potential new treatment options, which could substantially ease the burden of Crohn’s disease,” Dr Lee said. “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.”