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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

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Authors

Manuel A. Rivas

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 28, 2024
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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