A series of genetic variants that affect the severity of Crohn’s disease have been identified, but none is related to a person’s risk of developing the condition, say researchers.
Crohn’s disease is one chronic complex disease that is not caused by a single gene – about 170 common genetic variants have been identified that each increase the risk of an individual developing the disease.
However, research published in the latest edition of Nature Genetics by a team led by the University of Cambridge, UK, demonstrated genetic variants that affect the progression of a disease operate independently of those that increase the likelihood of developing the disease in the first place.
Dr James Lee from the Department of Medicine at Cambridge said while genetic studies have identified genetic risk factors for Crohn’s disease, mystery still surrounds the reasons why the disease progresses differently among individuals.
“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,” he said.
For the study, the team examined the genomes of more than 2,700 individuals, each of whom had either suffered very mild or very aggressive Crohn’s disease.
When their DNA was compared, they found four genetic variants that influenced the severity of a patient’s condition, none of which affect the risk of developing the disease.
When the researchers went on to examine all the known genetic risk variants for Crohn’s, they found that none of these influenced the severity of disease.
Professor Ken Smith, head of the Department of Medicine, said the findings were unexpected because they showed that the genetic architecture of disease outcome is different from disease risk.
“In other words, the biological pathways driving disease progression may be very different to those that initiate the disease itself. This was quite unexpected,” he said.
“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.”
One of the genetic variants discovered by the team was in the gene FOXO3, which is involved in modulating the release of the cytokine TNFa. FOXO3-TNFa pathway is also known to affect the severity of rheumatoid arthritis.
Another of the variants was close to the gene IGFBP1, which plays a role in the immune system. This genetic region has also been linked to rheumatoid arthritis.
The third genetic variant was found in the MHC region, which determines how our immune cells respond to invading organisms and has been linked to a number of auto-immune diseases, including Crohn’s. However, the genetic variant that alters Crohn’s disease risk is different from the one that affects prognosis.
The fourth variant was found in the gene XACT. Very little is known about this gene, although it seems to be mainly active in cells in the intestine.
Dr Lee said the findings could lead to new treatment options.
“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,” he added.
Lee JC, Biasci D, et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn’s disease. Nature Genetics 9 January 2017; doi: 10.1038/ng.3755
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