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Nature Research (part of Springer Nature), Nature Communications, (7), p. 12342

DOI: 10.1038/ncomms12342

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A protein truncating R179X variant in RNF186 confers protection against ulcerative colitis

Journal article published in 2015 by K. de Lange, K. de Lane, Manuel A. Rivas, Daniel Graham, Patrick Sulem ORCID, Christine Stevens, A. Nicole Desch, A. Nicole Desch, Philippe Goyette, Daniel Gudbjartsson ORCID, Ingileif Jonsdottir, Mauro D’amato, Soren Mucha, Unnur Thorsteinsdottir, Frauke Degenhardt and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Data provided by SHERPA/RoMEO

Abstract

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10−7, odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.