Scientists crack open genetic roots behind Crohn’s disease

The cause of Crohn’s disease remains not well-understood, but scientists have gathered that it may be triggered by diet and lifestyle. A group of international scientists are adding more pieces to the puzzle, though, successfully identifying variants in 10 genes that heighten risk of developing Crohn’s disease.

Crohn’s disease affects the lives of over half a million people in the United States, often causing immense abdominal pain due to chronic inflammation in the gut. Researchers from the Wellcome Sanger Institute and the Broad Institute have now conducted this study to identify rare genetic variants within protein-coding genes that are associated with Crohn’s disease risk. They did this by performing exome sequencing — a technique used to sequence all protein-coding regions of genes in a genome — on about 30,000 Crohn’s patients and 80,000 without the disease.

Study authors were able pick up on a variation in six genes in regions that had not been previously associated with Crohn’s disease, leading to valuable findings.

“Most humans will have some of the genetic variants that increase susceptibility to inflammatory bowel disease because they’re so common. These common variants may increase a person’s risk by 10 percent, for example, but this increased risk doesn’t necessarily lead to disease,” says Dr Aleksejs Sazonovs, a first author of the study from the Wellcome Sanger Institute, in a statement. “But some rare variants can make someone four or five times more likely to develop inflammatory bowel disease, so it’s especially important to locate these and understand the biological processes they disrupt.”

One rare variant in a gene referred to as TAGAP was found to decrease a person’s risk of developing Crohn’s disease. Other variants like this, called “protective mutations,” are what researchers want to keep a watch for because it provides a way to discover a mechanism that can deactivate the gene.

Ultimately, this can help develop drugs that can mimic the mutation by potentially disabling the protein that the specific gene codes, without adverse side effects.

“In thinking about how to develop new therapies, it’s critical that we can pinpoint the specific genetic variants that increase or decrease a person’s risk. When we discover a disease association to a genetic variant within a gene, we can start running experiments the next day to figure out what the variant, the gene, and the protein it encodes is doing to influence disease risk,” explains Dr. Mark Daly, a senior author of the study from the Broad Institute of MIT and Harvard.

Now, the research team hopes to expand their efforts to ulcerative colitis and expand sampling to cover inflammatory bowel disease as a whole. They stress that including thousands of participants is vital to the advancement of this area of research, and so they hope that collaborating internationally continues to be a priority in making these works happen.

This study is published in the journal Nature Genetics.

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