Researchers Find Biological Basis For Crohn’s Association

Just about every week a new genome-wide association study links common variations in the genome to some disease. But only rarely do the authors of these studies have more than a guess of why these SNPs are associated with a particular condition.

On Sunday in the online edition of Nature Genetics, researchers presented results that may bring them closer (though not all the way) to understanding one SNP recently associated with Crohn’s disease.

Each copy of a C at rs13361189 increases a person’s risk of developing Crohn’s disease 1.33 times compared to someone with two copies of a T. This SNP lies very close to IRGM, a gene for a protein involved in clearing out bacteria that invade cells. A SNP in another gene involved in this same process, known as autophagy, has also been linked to Crohn’s disease.

(23andMe customers can check their data at substitute SNP rs7714584. The G version is linked with an increased risk for Crohn’s disease.)

It makes sense that genes involved in autophagy would influence a person’s risk for Crohn’s, because the body’s ability deal with bacteria in the intestines is thought to be at the heart of this inflammatory bowel disease. Yet studies have failed to find anything in the IRGM gene itself that could account for this particular SNP’s association with Crohn’s.

McCarroll et al show in their current study that people with the C version of rs13361189 also have a large deletion of about 20,000 DNA bases in front of the IRGM gene that people with the T version (A for 23andMe customer’s looking at their data for rs7714584) don’t have.

The deletion appears to regulate how much protein is made from the IRGM protein, although exactly how it does this is not clear. In laboratory tests the deletion caused some cell types to make more protein, while others made less.

The researchers can’t say which direction the deletion is working in the intestines, but they do know that the amount of IRGM protein affects cells’ autophagy abilities. Lab tests also showed that cells with more IRGM are better able to engulf and destroy invasive bacteria compared to cells with less.

More research will be needed to fully understand the meaning of variations in the IRGM gene, as well as the more than thirty other SNPs so far associated with Crohn’s. As scientists begin to understand the functional consequences of the variations, they will gain valuable insight into the mechanisms of the disease that may some day lead them to new and better treatments.






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