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

Journal article

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.

Authors: Rivas, MA; Graham, D; Sulem, P; Stevens, C; Desch, AN

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Communications
• Volume: 7
• Article number: 12342
• Publication date: 2016-08-09
• Acceptance date: 2016-06-24
• DOI: 10.1038/ncomms12342
• ISSN: 2041-1723
• Pmid: 27503255
• Language: English
• Keywords: NIDDK IBD Genetics Consortium; UK IBD Genetics Consortium