Manuel A. Rivas
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Rivas, Manuel A.; Graham, Daniel; Sulem, Patrick; Stevens, Christine; Nicole Desch, A.; Goyette, Philippe; Gudbjartsson, Daniel; Jonsdottir, Ingileif; Thorsteinsdottir, Unnur; Degenhardt, Frauke; Mucha, S�ren; Kurki, Mitja I.; Li, Dalin; D�Amato, Mauro; Annese, Vito; Vermeire, Severine; Weersma, Rinse K.; Halfvarson, Jonas; Paavola-Sakki, Paulina; Lappalainen, Maarit; Lek, Monkol; Cummings, Beryl; Tukiainen, Taru; Haritunians, Talin; Halme, Leena; Koskinen, Lotta L.E.; Ananthakrishnan, Ashwin N.; Luo, Yang; Heap, Graham A.; Visschedijk, Marijn C.; IBD Genetics Consortium, UK; IBD Genetics Consortium, NIDDK; MacArthur, Daniel G.; Neale, Benjamin M.; Ahmad, Tariq; Anderson, Carl A.; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Cho, Judy H; Palotie, Aarno; Saavalainen, P�ivi; Kontula, Kimmo; F�rkkil�, Martti; McGovern, Dermot P.B.; Franke, Andre; Stefansson, Kari; Rioux, John D.; Xavier, Ramnik J.; Daly, Mark J.; Hawkey, Chris
Authors
Daniel Graham
Patrick Sulem
Christine Stevens
A. Nicole Desch
Philippe Goyette
Daniel Gudbjartsson
Ingileif Jonsdottir
Unnur Thorsteinsdottir
Frauke Degenhardt
S�ren Mucha
Mitja I. Kurki
Dalin Li
Mauro D�Amato
Vito Annese
Severine Vermeire
Rinse K. Weersma
Jonas Halfvarson
Paulina Paavola-Sakki
Maarit Lappalainen
Monkol Lek
Beryl Cummings
Taru Tukiainen
Talin Haritunians
Leena Halme
Lotta L.E. Koskinen
Ashwin N. Ananthakrishnan
Yang Luo
Graham A. Heap
Marijn C. Visschedijk
UK IBD Genetics Consortium
NIDDK IBD Genetics Consortium
Daniel G. MacArthur
Benjamin M. Neale
Tariq Ahmad
Carl A. Anderson
Steven R. Brant
Richard H. Duerr
Mark S. Silverberg
Judy H Cho
Aarno Palotie
P�ivi Saavalainen
Kimmo Kontula
Martti F�rkkil�
Dermot P.B. McGovern
Andre Franke
Kari Stefansson
John D. Rioux
Ramnik J. Xavier
Mark J. Daly
Chris Hawkey
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
Rivas, M. A., Graham, D., Sulem, P., Stevens, C., Nicole Desch, A., Goyette, P., …Hawkey, C. (2016). A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nature Communications, 7, 1-8. https://doi.org/10.1038/ncomms12342
Journal Article Type | Article |
---|---|
Acceptance Date | Jun 24, 2016 |
Online Publication Date | Aug 9, 2016 |
Publication Date | Aug 9, 2016 |
Deposit Date | Nov 24, 2016 |
Publicly Available Date | Mar 26, 2020 |
Journal | Nature Communications |
Electronic ISSN | 2041-1723 |
Publisher | Nature Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 7 |
Article Number | 12342 |
Pages | 1-8 |
DOI | https://doi.org/10.1038/ncomms12342 |
Public URL | https://nottingham-repository.worktribe.com/output/1118240 |
Publisher URL | https://www.nature.com/articles/ncomms12342 |
PMID | 00038095 |
Additional Information | Chris Hawkey part of UK IBD Genetics Consortium |
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