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RNA Editing Linked to Genetic Risk of Common Inflammatory Diseases

A common RNA modification that helps prevent errant immune responses underlies the genetic risk of many inflammatory diseases, according to a new study appearing in this week's Nature. Adenosine-to-inosine (A-to-I) RNA editing occurs when adenosine deaminases acting on RNA, or ADARs, bind to double-stranded RNA substrates and convert adenosines to inosines, a process that is vital for suppressing cellular dsRNA-mediated innate immune interferon responses. Previous research has linked A-to-I RNA editing and its enzymatic components to many common immune and inflammatory diseases, but the extent to which common genetic differences in RNA editing may contribute to these disorders remains unidentified. To investigate, a group led by scientists from Stanford University analyzed genomic and RNA sequence data across dozens of tissues from hundreds of participants in the Genotype-Tissue Expression project, focusing on how patterns of RNA editing vary between individuals to identify cis genetic variants associated with RNA editing. These variants — termed editing quantitative trait loci (edQTLs) — were found to be significantly enriched in genome-wide association study signals for autoimmune and immune-mediated diseases. "Colocalization analysis of edQTLs with disease risk loci further pinpointed key, putatively immunogenic dsRNAs formed by expected inverted repeat Alu elements, as well as unexpected, highly over-represented cis-natural antisense transcripts," the study's authors write. "Furthermore, inflammatory disease risk variants, in aggregate, were associated with reduced editing of nearby dsRNAs and induced interferon responses in inflammatory diseases." The findings, they conclude, reveals RNA editing as an important mechanism underlying the genetic risk for numerous immune-related diseases and points to the therapeutic potential of targeting dsRNA editing and sensing pathways.

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