Nature: Li Jin's team reveals RNA editing is the basis of genetic risk for common inflammatory diseases

The Human Genome Project (HGP) has successfully drawn the human genome map, and human beings have also obtained their own "natural book.

Today, genome-wide association studies (GWAS) have identified hundreds of thousands of risk variants associated with traits and disease etiology, and quantitative trait locus (QTL) studies have successfully linked GWAS variants to their molecular mechanism.

Recently, the team of Professor Jin Billy Li from the Department of Genetics of Stanford University (Li Qin is the first author) published a paper in Nature entitled: RNA editing underlies genetic risk of common inflammatory disease.

This study demonstrates that adenosine-inosine (A→I) RNA editing mediated by the RNA editing protein ADAR is an important post-transcriptional event that prevents the cell's own double-stranded RNA (dsRNA) from triggering an innate immune interferon response, caused by genetic factors Decreased levels of double-stranded RNA editing are an important factor in increasing the genetic risk of inflammatory disease.

The innate immune system is the vanguard of the body's fight against viral infections, in which MDA5 is an intracellular dsRNA monitor that senses viral dsRNA and then produces interferons required for anti-viru.

Adenosine deaminase (ADAR) is an RNA editing enzyme that catalyzes the deamination of adenosine (A) of dsRNA to inosine (I.

As early as 2015, Professor Li Jin's team published a paper in Science [2], revealing that ADAR gene-deficient mice died at embryonic day 15 and exhibited multi-organ inflammatory responses caused by interferon immune response.

In this latest study, the research team used data from the GTEx project to examine the genome and RNA sequences of 49 human tissues from 838 people, and analyzed how RNA editing patterns varied between individuals to identify cis-parameters associated with RNA editin.

The research team identified a total of 30,319 edQTLs with cis-regulatory effects on RNA editing levels, of which nearly one-third were tissue-specifi.

ADAR edits endogenous dsRNA to avoid autoimmune response

To assess the potential role of changes in RNA editing levels caused by edQTLs in common genetic diseases and traits, the research team performed a combined analysis of data from multiple GWAS studie.

This indicated that edQTLs associated with decreased RNA editing levels were significantly different among different organs and tissues, and were especially highly enriched in immune tissues and immune-disease-associated tissue.

edQTLs associated with decreased RNA editing levels are highly enriched in immune and immune-disease-associated tissues

Based on this, the research team further conducted co-localization analysis of 17 immune-related diseases and edQTL, and identified 194 immunogenic dsRNAs, of which 178 (92%) were located in exonic regions, especially in UTR.

Most (92%) of immunogenic dsRNAs are located in exonic regions

To further search for evidence in disease tissue, the researchers performed allele-specific RNA editing (ASED) analysis on hundreds of patient sample.

More interestingly, more than 95% of RNA editing sites in the human transcriptome are located in inverted repeats, but the team was surprised to find that about 33% of the 194 immunogenic dsRNAs were located in protein-coding region.

Risk variants in inflammatory diseases are associated with reduced levels of nearby dsRNA editing and induction of interferon responses

Collectively, this study demonstrates that reduced levels of dsRNA editing caused by genetic variation are an important mechanism in the initiation of autoimmune and inflammatory disease.

Decreased levels of dsRNA editing due to genetic variation trigger autoimmune disease

Not only that, this discovery also provides new ideas for the screening, diagnosis and treatment of autoimmune and inflammatory diseases, suggesting that inhibiting the abnormal activation of MDA5 in disease-related tissues and cells may be a potential new targe.

Original source:

Li, .
, Gloudemans, MJ, Geisinger, JM et a.
RNA editing underlies genetic risk of common inflammatory disease.
Nature (2022.
https://do.
org/11038/s41586-022-05052-.