Clues to celiac disease found in ‘junk RNA’

Celiac disease is a relatively common immune disorder, affecting an estimated 1 in 250 Americans. The exact causes of the disease are still shrouded in mystery; new research, published in Science, uncovers a potential link with so-called junk RNA in the human genome.
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Celiac disease affects millions of people worldwide. Fresh investigations involving RNA find new clues to its origin.

Individuals with celiac disease generate an allergic response to the gluten found in wheat, barley and rye.

This inappropriate reaction disturbs the hair-like projections of the small intestine – villi – causing symptoms that include bloating, anemia, fatigue, diarrhea and weight loss.

Over time, the inflammation caused by gluten-sensitive T cells permanently damages the lining of the small intestine.

In the long term, celiac disease can lead to problems with the nervous system, bones and other organs. In children, it can slow growth rates and present severe discomfort.

Genetics and celiac disease

Although there is no known cure for celiac disease, some risk factors are known; these include type 1 diabetes, Down’s syndrome and autoimmune thyroid disease. Additionally, there is a strong familial connection – people with a first-degree relative with the disease (parent, child, sibling) have a 1 in 10 chance of developing celiac disease.

The hereditary nature of celiac disease has inspired scientists to probe for a specific genetic component.

Researchers have uncovered one such gene variant in a sequence known as lnc13. The lnc13 variant is known to be present in 40% of the population, but, surprisingly, only 1% of carriers go on to develop an immune reaction to the protein gluten. This has perplexed researchers.

Co-author of the current study Dr. Peter Green, of Columbia University Medical Center (CUMC) in New York, says:

“We don’t know why only a fraction of individuals with genetic risk factors for celiac disease actually become gluten intolerant.”

Looking for solutions in the gaps

With the ever-increasing power of modern research techniques, the mysteries of genetics are slowly being unlocked. Already, scores of species have had their entire genomes sequenced. As the information pours in, uncovering each gene’s role is the next phase of the challenge.

On this journey through the genome, the prevalence of “junk” sequences has become apparent. These were initially referred to as “junk” because they do not code for a specific protein.

In the past, it was the protein-coding ability of DNA and RNA that was considered the primary role of the genome. However, this large quantity of seemingly redundant code is now known to be essential in other processes. Junk sequences, now referred to as non-coding RNA (ncRNA), are abundant, making up the majority of our genome.

Some sections of ncRNA have been highly preserved throughout eons of evolution; it is, therefore, a safe assumption that they play vital roles.

Researchers are yet to chart the full impact of these ncRNA molecules, but they are thought to play a number of regulatory roles. The celiac sequence, lnc13, is part of a subset of ncRNA molecules called long noncoding RNA (lncRNA); they are so-called because they are relatively long, containing more than 200 nucleotide building blocks per strand.

Scientists believe that lncRNAs might play a role in autoimmune diseases and cancers by interacting and regulating RNA, DNA and proteins.

Celiac disease and lnc13

In a suite of molecular experiments, the team at CUMC showed that the normal version of lnc13 suppresses the expression of celiac-associated genes by binding to a family of proteins.

However, the lnc13 variant associated with celiac disease does not bind so tightly to this group of proteins. This weaker bond causes an increase in the expression of genes related to inflammatory responses.

In another arm of the investigation, the team found that individuals with celiac disease had significantly lower levels of lnc13 in their guts; this infers a potential role in the inflammation response of the disease.

Lead author Sankar Ghosh says of the results:

“These findings add an important detail to our understanding about how celiac disease develops […] 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.”

The new findings surrounding lnc13 are the beginning of a long road to understanding the disease, but the team is committed to forging ahead. As Dr. Green says: “It is only through the dedicated work of translational scientists that we can begin to uncover the mechanisms that unleash the symptoms of celiac disease.”

Medical News Today recently covered research investigating the role of gut bacteria in celiac disease.

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