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Crohn's risk, prognosis associated with distinct genetic variants
Genetic variants impacting the risk for developing Crohn’s disease and those influencing the progression and severity of the disease exist independently of one another, according to a research letter published in Nature Genetics.
“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,” James Lee, MD, from the department of medicine at the University of Cambridge in the U.K., said in a press release. “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.”
Therefore, to better understand the genetic variants that influence progression of Crohn’s disease, Lee and colleagues performed a genome-wide association study of more than 2,700 patients grouped by good vs. poor disease prognosis, and performed a meta-analysis of their findings.
They found that none of the 170 known IBD susceptibility loci were associated with IBD prognosis. In addition, they identified four genome-wide significant loci associated with IBD severity, none of which were associated with IBD susceptibility.
“This shows us that the genetic architecture of disease outcome is very different to that of disease risk,” Ken Smith, MD, head of the department of medicine at Cambridge, said in the press release. “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.”
The four genetic loci associated with IBD prognosis included the FOXO3 gene, involved in modulating TNF-alpha and known to influence the severity of rheumatoid arthritis; a region near the IGFBP1 gene, also associated with rheumatoid arthritis and known to be involved in the immune system; the MHC region, also involved with the immune system and implicated in other autoimmune diseases; and the XACT gene, which is poorly understood but appears to be primarily active in the intestine.
“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,” Lee said in the press release. “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.” – by Adam Leitenberger
Disclosures: The researchers report no relevant financial disclosures.