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Celiac Disease Linked to Common Variant in Long Non-Coding RNA

NEW YORK (GenomeWeb) – A research team led by investigators from Columbia University have identified a common variant in a long non-coding RNA called lnc13 that may contribute to the inflammation that is characteristic of celiac disease.

Celiac disease is an autoimmune digestive disorder that causes genetically predisposed individuals to develop an immune response to gluten. Although an estimated 40 percent of the population has the primary gene variant associated with the disease, only one percent of people with the gene variant actually develop intestinal inflammation and damage after ingesting gluten. 

"We don't know why only a fraction of individuals with genetic risk factors for celiac disease actually become gluten intolerant," author Peter Green, a professor of medicine at Columbia University Medical Center and director of the Celiac Disease Center at Columbia University, said in a statement.

As they reported today in Science, the researchers found that "recent studies have revealed 39 non-human lymphocyte antigen regions associated with a risk of [celiac disease] development, including many in non-coding regions." Previous studies in mice have indicated that regions of long non-coding RNA (lncRNA) play a role in autoimmune disease and cancers by interacting with other RNA, DNA, and proteins. In particular, recent research has found that a single-nucleotide polymorphism variant in lnc13 in the mouse genome was associated with celiac disease in mice.

For this study, the researchers decided to focus on the same lncRNA region in humans to see if the links to celiac disease risk were also observable on lnc13 in the human genome. They began by attempting to characterize the region, looking closely at the regions in both mice and humans and performing a variety of analyses — including intestinal RNA sequencing, in situ hybridization, histone modification analysis, chromatin signature analysis, and looking at deoxyribonuclease hypersensitivity site data.

The researchers found that there is celiac-associated SNP variant in lnc13. Normally, lnc13 dampens the expression of celiac-associated genes. When the variant is present, lnc13 binds poorly to a common family of proteins and caused increased expression of inflammatory genes noted to be present in celiac patients. They also discovered that celiac patients had unusually low levels of lnc13 in their intestines, which suggest that its downregulation may contribute to inflammation seen in the disease.

"Given that the majority of the population consumes these grains, understanding the factors that put certain individuals at greater risk for the development of celiac disease will have a broad impact," lead author Sankar Ghosh, professor and chairman of the Department of Microbiology and Immunology at Columbia University Medical Center, said in a statement. "In future studies, we hope to investigate factors that lead to suppression of lnc13, which may cause celiac disease in people who were previously able to tolerate gluten."