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This study analyzed A-to-I RNA editing patterns in kidney tissue from 215 patients with nephrotic syndrome, examining both individual editing sites and clusters of nearby editing sites. Researchers found that higher levels of clustered RNA editing in the tubulointerstitium were associated with reduced interferon activity, lower proteinuria, and better kidney function. The study identified hundreds of genetic variants that regulate RNA editing and discovered that analyzing editing sites as clusters revealed additional genetic signals and disease associations not detectable when examining individual sites alone.
Why it matters
RNA editing may represent a protective mechanism in kidney disease by dampening inflammatory responses. The identification of genetic variants controlling RNA editing could help explain why some patients experience worse kidney disease outcomes and potentially lead to new biomarkers or therapeutic targets for nephrotic syndrome.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
INTRODUCTION RNA editing has been implicated in endogenous double-stranded RNA (dsRNA) sensing and inflammatory disease, but its prevalence, genetic regulation, and consequences in diseased human kidney tissue have not been systematically characterized. Because ADAR enzymes edit multiple neighboring adenosines often in the same transcript, analyzing these sites holistically (as "clusters") may reveal effects missed by single-site analysis. METHODS We profiled both single-site and cluster A-to-I RNA editing in the kidneys of 215 participants from the Nephrotic Syndrome Study Network with focal segmental glomerulosclerosis or minimal change disease who had microdissected glomerular and/or tubulointerstitial RNA-seq and blood genome sequencing. We tested single-site and cluster editing association with estimated glomerular filtration rate, proteinuria, and an interferon stimulated gene expression score. To discover the genetic determinants of editing, we conducted mapping of both single-site, cis-editing QTL and cluster-level editing QTLs (cledQTLs). We then tested cledQTLs for colocalization with kidney eQTLs and kidney-relevant GWAS. RESULTS Greater cluster mean editing in tubulointerstitium was associated with lower interferon-stimulated gene activity (P = 4.81 x 10-9), lower UPCR (P = 0.01) and higher eGFR (P = 8.52 x 10-5). Genetic mapping identified 290 glomerular and 473 tubulointerstitial single-site edQTLs, as well as 21 glomerular and 51 tubulointerstitial cledQTLs. We identified 10 colocalized signals between cledQTL and GWAS and 14 between cledQTL and eQTL. Nine of 51 tubulointerstitial cledQTL clusters were individually associated with eGFR in NEPTUNE. CONCLUSION These results identify A-to-I RNA editing as a measurable and partly genetically regulated molecular phenotype in proteinuric kidney disease and nominate clustered editing of tubulointerstitial transcripts as a putative contributor to attenuated immune activity and higher kidney function. Cluster-level analysis identified additional genetically regulated editing patterns and colocalized signals not detected at individual sites, highlighting the added value of analyzing nearby editing sites as clusters.
Source: A-to-I RNA editing in kidney tissue from patients with nephrotic syndrome