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

2.50
Hdl Handle:
http://hdl.handle.net/11287/619885
Title:
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
Authors:
Rivas, M A; Graham, D; Sulem, P; Stevens, C; Desch, A N; Goyette, P; Gudbjartsson, D; Jonsdottir, I; Thorsteinsdottir, U; Degenhardt, F; Mucha, S; Kurki, M I; Li, D; D'Amato, M; Annese, V.; Vermeire, S; Weersma, R K; Halfvarson, J.; Paavola-Sakki, P; Lappalainen, M; Lek, M; Cummings, B; Tukiainen, T; Haritunians, T; Halme, L; Koskinen, L L E; Ananthakrishnan, A N; Luo, Y; Heap, Graham A.; Visschedijk, M C; MacArthur, D G; Neale, B M; Ahmad, Tariq; Anderson, C A; Brant, S R; Duerr, R H; Silverberg, MS; Cho, J H; Palotie, A.; Saavalainen, P; Kontula, K; Färkkilä, M; McGovern, D P B; Franke, A; Stefansson, K; Rioux, J D; Xavier, R J; Daly, M J; Barrett, J; de Lane, K; Edwards, C; Hart, A; Hawkey, C; Jostins, L; Kennedy, N; Lamb, C; Lee, J; Lees, C; Mansfield, J; Mathew, C; Mowatt, C; Newman, B; Nimmo, E; Parkes, M; Pollard, M; Prescott, N; Randall, J; Rice, D; Satsangi, J; Simmons, A; Tremelling, M; Uhlig, H; Wilson, D; Abraham, C; Achkar, J P; Bitton, A; Boucher, G; Croitoru, K; Fleshner, P; Glas, J; Kugathasan, S; Limbergen, J V; Milgrom, R; Proctor, D; Regueiro, M; Schumm, P L; Sharma, Y; Stempak, J M; Targan, S R; Wang, M H
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.
Citation:
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. 2016, 7:12342 Nat Commun
Publisher:
Nature
Journal:
Nature Communications
Issue Date:
Aug-2016
URI:
http://hdl.handle.net/11287/619885
DOI:
10.1038/ncomms12342
PubMed ID:
27503255
Additional Links:
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27503255/
Note:
This article is freely available via PubMed Central. Click on the Additional Link to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
2041-1723
Appears in Collections:
Gastroenterology; 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorRivas, M Aen
dc.contributor.authorGraham, Den
dc.contributor.authorSulem, Pen
dc.contributor.authorStevens, Cen
dc.contributor.authorDesch, A Nen
dc.contributor.authorGoyette, Pen
dc.contributor.authorGudbjartsson, Den
dc.contributor.authorJonsdottir, Ien
dc.contributor.authorThorsteinsdottir, Uen
dc.contributor.authorDegenhardt, Fen
dc.contributor.authorMucha, Sen
dc.contributor.authorKurki, M Ien
dc.contributor.authorLi, Den
dc.contributor.authorD'Amato, Men
dc.contributor.authorAnnese, V.en
dc.contributor.authorVermeire, Sen
dc.contributor.authorWeersma, R Ken
dc.contributor.authorHalfvarson, J.en
dc.contributor.authorPaavola-Sakki, Pen
dc.contributor.authorLappalainen, Men
dc.contributor.authorLek, Men
dc.contributor.authorCummings, Ben
dc.contributor.authorTukiainen, Ten
dc.contributor.authorHaritunians, Ten
dc.contributor.authorHalme, Len
dc.contributor.authorKoskinen, L L Een
dc.contributor.authorAnanthakrishnan, A Nen
dc.contributor.authorLuo, Yen
dc.contributor.authorHeap, Graham A.en
dc.contributor.authorVisschedijk, M Cen
dc.contributor.authorMacArthur, D Gen
dc.contributor.authorNeale, B Men
dc.contributor.authorAhmad, Tariqen
dc.contributor.authorAnderson, C Aen
dc.contributor.authorBrant, S Ren
dc.contributor.authorDuerr, R Hen
dc.contributor.authorSilverberg, MSen
dc.contributor.authorCho, J Hen
dc.contributor.authorPalotie, A.en
dc.contributor.authorSaavalainen, Pen
dc.contributor.authorKontula, Ken
dc.contributor.authorFärkkilä, Men
dc.contributor.authorMcGovern, D P Ben
dc.contributor.authorFranke, Aen
dc.contributor.authorStefansson, Ken
dc.contributor.authorRioux, J Den
dc.contributor.authorXavier, R Jen
dc.contributor.authorDaly, M Jen
dc.contributor.authorBarrett, Jen
dc.contributor.authorde Lane, Ken
dc.contributor.authorEdwards, Cen
dc.contributor.authorHart, Aen
dc.contributor.authorHawkey, Cen
dc.contributor.authorJostins, Len
dc.contributor.authorKennedy, Nen
dc.contributor.authorLamb, Cen
dc.contributor.authorLee, Jen
dc.contributor.authorLees, Cen
dc.contributor.authorMansfield, Jen
dc.contributor.authorMathew, Cen
dc.contributor.authorMowatt, Cen
dc.contributor.authorNewman, Ben
dc.contributor.authorNimmo, Een
dc.contributor.authorParkes, Men
dc.contributor.authorPollard, Men
dc.contributor.authorPrescott, Nen
dc.contributor.authorRandall, Jen
dc.contributor.authorRice, Den
dc.contributor.authorSatsangi, Jen
dc.contributor.authorSimmons, Aen
dc.contributor.authorTremelling, Men
dc.contributor.authorUhlig, Hen
dc.contributor.authorWilson, Den
dc.contributor.authorAbraham, Cen
dc.contributor.authorAchkar, J Pen
dc.contributor.authorBitton, Aen
dc.contributor.authorBoucher, Gen
dc.contributor.authorCroitoru, Ken
dc.contributor.authorFleshner, Pen
dc.contributor.authorGlas, Jen
dc.contributor.authorKugathasan, Sen
dc.contributor.authorLimbergen, J Ven
dc.contributor.authorMilgrom, Ren
dc.contributor.authorProctor, Den
dc.contributor.authorRegueiro, Men
dc.contributor.authorSchumm, P Len
dc.contributor.authorSharma, Yen
dc.contributor.authorStempak, J Men
dc.contributor.authorTargan, S Ren
dc.contributor.authorWang, M Hen
dc.date.accessioned2016-09-06T13:18:52Z-
dc.date.available2016-09-06T13:18:52Z-
dc.date.issued2016-08-
dc.identifier.citationA protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. 2016, 7:12342 Nat Communen
dc.identifier.issn2041-1723-
dc.identifier.pmid27503255-
dc.identifier.doi10.1038/ncomms12342-
dc.identifier.urihttp://hdl.handle.net/11287/619885-
dc.description.abstractProtein-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.en
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27503255/en
dc.rightsArchived with thanks to Nature communications. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/en
dc.subjectWessex Classification Subject Headings::Gastroenterologyen
dc.titleA protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.en
dc.typeJournal Articleen
dc.identifier.journalNature Communicationsen
dc.description.noteThis article is freely available via PubMed Central. Click on the Additional Link to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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