- The severity of Crohn's disease varies from one individual to another.
- Four genetic variants that decide the severity of the disease has been identified.
- These genetic variants do not increase the individual's risk of developing the condition.
A different set of genes that affect the severity of Crohn's disease have been identified.
These genetic variants are not related to the original variants and do not increase the individual's risk of developing the condition in the first place.
‘The newly discovered genetic variants opens up potential new treatment options, which could substantially ease the burden of Crohn's disease.’
Crohn's disease is an inflammation of the digestive system can affect any area from the mouth to the anus. It often affects the lower part of the small intestine called the ileum.
It is among a group of diseases called inflammatory bowel disease (IBD), the other one being ulcerative colitis.
It most commonly starts between the ages of 13 and 30. The most common symptoms are pain in the abdomen and diarrhea. Other symptoms include bleeding from the rectum weight loss and fever.
In the United States, it is currently estimated that about 1 -1.3 million people suffer from IBD.
There number of existing cases of Crohn's disease per 100,000 adults is 201. There are 3.1 to 14.6 newly diagnosed cases per 100,000 persons.
These is no single gene that causes the disease. To date around 170 common genetic variants have been identified that each increase the risk of an individual developing the disease.
The conventional belief is that 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.
Studying the Variants
A team of researchers led by the University of Cambridge has shown that the 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." Lee added.
For the study, the researchers looked at the genomes of more than 2,700 individuals. These individuals had either experienced particularly mild or particularly aggressive Crohn's disease.
On comparing these patients' DNA, the researchers found four genetic variants that influenced the severity of a patient's condition.
But none of these variants affected the risk of developing the disease.
The previously discovered genetic variants did not influence 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 focused 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." Smith added.
- This genetic variant modulates the release of the cytokine TNFα.
Cytokines are proteins released in response to infection or, inflammatory conditions like Crohn's disease or auto-inflammtory conditions where body attacks itself. These are released into the blood by immune cells.
This FOXO3-TNFα pathway is also known to affect the severity of rheumatoid arthritis which is an auto-inflammatory disease.
- The second variant was close to the gene IGFBP1. This genetic region has previously been linked to rheumatoid arthritis. It releases a particular antibody and the presence of this antibody is associated with more severe disease.
- The third genetic variant was in the MHC region. It is responsible for determining how our immune cells respond to invading organisms. The genetic variant the team identified was associated with a milder course of Crohn's disease.
- Very little is known about this variant. But 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 is published in Nature Genetics
- Epidemiology of the IBD - (https://www.cdc.gov/ibd/ibd-epidemiology.htm)
- Crohn's Disease - (https://medlineplus.gov/crohnsdisease.html)
- James Lee et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nature Genetics ; (2017)