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A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Broad Institute, Massachusetts Institute of Technology, Cambridge MA, USA; Broad Institute, Harvard University, Cambridge MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Broad Institute, Massachusetts Institute of Technology, Cambridge MA, USA; Broad Institute, Harvard University, Cambridge MA, USA;.
deCODE Genetics, Amgen Inc., Reykjavik, Iceland.
Broad Institute, Massachusetts Institute of Technology, Cambridge MA, USA; Broad Institute, Harvard University, Cambridge MA, USA;.
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12342Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
London, United Kingdom: Nature Publishing Group, 2016. Vol. 7, article id 12342
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-51667DOI: 10.1038/ncomms12342ISI: 000380952600001PubMedID: 27503255Scopus ID: 2-s2.0-84981165781OAI: oai:DiVA.org:oru-51667DiVA, id: diva2:955171
Note

Funding Agencies:

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869  DK062432

National Human Genome Research Institute (NHGRI) DK064869  DK043351  HG005923

Crohns and Colitis Foundation 3765

Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001

Amgen 2013583217

CCFA 3765

Cedars-Sinai F. Widjaja Foundation

European Union DK062413  AI067068  U54DE023789-01  305479

Leona M. and Harry B. Helmsley Charitable Trust

Crohn's and Colitis Foundation of America

NIH DK062431  U01 DK062429  U01 DK062422  R01 DK092235  U01 DK062420

Medical Research Council, UK MR/J00314X/1

Wellcome Trust WT091310  098051

Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763

Available from: 2016-08-24 Created: 2016-08-16 Last updated: 2018-07-16Bibliographically approved

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Halfvarson, Jonas

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