NEW YORK (GenomeWeb) – Researchers have conducted RNA sequencing on celiac disease samples, unearthing genetic signatures that could help identify potential therapies for these patients.
Led by investigators from Harvard Medical School and Regeneron Pharmaceuticals, the team used gene expression signatures in intestinal samples to get a closer look at the pathways involved in celiac disease in general, as well as expression changes specific to active forms of the immune-related gluten intolerance condition.
"Our findings provide the framework for future validation studies to investigate the early steps in celiac disease pathogenesis and to examine the remission state," first author Maureen Leonard, clinical director of the Mass General Hospital for Children Center for Celiac Research and Treatment, said in a statement.
For the study, published yesterday in PLOS One, Leonard and other investigators at the Mass General Hospital for Children and elsewhere collaborated with Regeneron to do RNA sequencing on intestinal biopsy samples from a dozen individuals with active celiac disease, 15 celiac disease-free controls, and 15 individuals with celiac disease who were in remission and showed no lasting intestinal damage.
"By performing RNA sequencing, we have uncovered additional genetic 'signatures' and moved closer to identifying targets for future therapeutic agents — in celiac disease and possibly other autoimmune conditions," Leonard said.
Along with innate immune gene expression changes present in both active cases and cases in remission, for example, the team identified immune response, cell adhesion, and spliceosome genes that appeared to be found at higher-than-usual levels in intestinal tissues from individuals with active celiac diseases.
"[T]hrough a focus on molecular signatures that are conserved in patients with [celiac disease] regardless of the disease activity and those signatures that differentiate active [celiac disease] from [celiac disease] in remission," the authors wrote, "we shed light on constitutively-involved pathways that may be at play not only in [celiac disease] but also in other chronic inflammatory diseases."
Past studies have unearthed some 57 genes outside of the human leukocyte antigen (HLA) immune region that have apparent ties to celiac disease risk, the team noted. Even so, risk factors found within and outside of the HLA so far seem to explain less than half of the heritability reported for celiac disease in prior family studies.
For the new analysis, the researchers used Illumina paired-end reads to do transcriptome-wide RNA sequencing on samples from individuals with or without active celiac disease, focusing on samples from the duodenum portion of the small intestine. With the transcriptome data, they focused on an immune-related gene signature that appeared to distinguish between active celiac cases and those in remission.
The team also did HLA typing or RNA sequencing on whole blood samples from the participants, confirming key expression shifts in the celiac disease samples with RT-PCR.
While all of the celiac cases appeared to have altered innate immune activity in the gut, the researchers identified shifts that were specific to the active celiac disease patients: among them, changes in the expression of mucosal cell adhesion, cell cycle, cytokine and chemokine signaling genes — findings that largely lined up with genome-wide association studies and immunological analyses of celiac disease that were published previously, they noted.
"Together, our findings support a possible link between the microbiome, innate immune response, and the development of [celiac disease]," the authors wrote, "and highlight possible associations that, with future validation, may lead to crucial knowledge of the steps leading to loss of tolerance to gluten."