Researchers struggling to find genes linked to celiac disease may have been looking in the wrong place. Recent findings have uncovered a gene that appears to amplify risk for the common autoimmune disorder by spelling out not a protein, but instead a noncoding RNA that keeps inflammatory genes in check.
That RNA, called lnc13, is missing or altered in people with celiac disease, which likely promotes their out-of-proportion immune response to wheat gluten, says study author Sankar Ghosh, an immunologist at Columbia University in New York. The findings appeared in the April 1, 2016 issue of Science.
Ghosh followed up on the work of scientists who scanned the genomes of people with celiac disease, hunting for single-letter changes in their DNA code. They found about 40 regions of the genome associated with higher risk for the disease. However, such studies only offer up an approximate address for the actual mutations that confer higher celiac disease risk. Fourteen of the genetic misspellings linked to celiac disease appear to be located within stretches of DNA that code for no known protein.
Those non-protein-coding mutations got little attention, Ghosh says, in the case of celiac or many other diseases where scientists have collected risk variants. He suspected they might occur in enhancer regions that control expression of protein-coding genes. He found a type of enhancer to look for in a 2009 paper cataloging long noncoding RNAs, lncRNAs for short (pronounced “link RNAs”). Once copied from the DNA, lncRNAs are often located in the nucleus, where they attach to other target genes to control whether they are on or off.
To test his idea, Ghosh compared the genetic addresses associated with celiac disease and the known locations of lncRNAs. He discovered lnc13 contains several sites that are mutated in some people with celiac disease. He then checked lnc13 RNA in gut biopsies from people with celiac disease. “It was dramatic what we observed,” Ghosh says. Compared to controls, people with celiac disease had barely any lnc13.
Ghosh’s hunt for disease-linked mutations beyond the protein-coding regions of the genome is exactly what scientists ought to be doing to find the genes for many diseases, not just celiac, says John Rinn, a molecular biologist at Harvard University in Cambridge, Massachusetts. Rinn co-authored the 2009 lncRNA paper but who was not involved in the Science study. “We can start to dig into this mysterious land that’s been neglected,” he says.
Since celiac is an immune disorder, Ghosh suspected lnc13 RNA might stifle inflammatory genes in the immune cells called macrophages. They discovered the lncRNA attached to gene-regulating proteins and a handful of genes that normally trigger inflammation. But when the scientists added a bit of bacterial cell wall, as if the macrophages were under attack, the cells destroyed lnc13 RNA as they turned on their immune response.
The authors suggest that, normally, lnc13 keeps inflammation down, and disappears when immune cells activate. But in people with celiac disease, the lncRNA is mostly absent. In people with the celiac-linked lnc13 mutations, the remaining lnc13 is also malformed, the scientists found, and does not bind to gene-regulating proteins properly. Ghosh suspects the loss of normal lnc13 makes people susceptible to developing celiac.
Rinn and Ghosh think that low levels of lnc13 in biopsy samples could make a useful test for celiac disease, which is difficult to diagnose. And lnc13 also might be involved in other inflammatory diseases, such as inflammatory bowel disease, Ghosh speculates. Next he will investigate is how different lncRNAs get their specificity, such that each turns off only certain genes.