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

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms12342

2041-1723

Manuel A. Rivas, Daniel B. Graham, Patrick Sulem, Christine Stevens, A. Nicole Desch, Philippe Goyette, Daníel F. Guðbjartsson, Ingileif Jónsdóttir, Unnur Þorsteinsdóttir, Frauke Degenhardt, Sören Mucha, Mitja Kurki, Dalin Li, Mauro D’Amato, Vito Annese, Séverine Vermeire, Rinse K. Weersma, Jonas Halfvarson, Paulina Paavola–Sakki, Maarit Lappalainen, Monkol Lek, Beryl B. Cummings, Taru Tukiainen, Talin Haritunians, Leena Halme, Lotta L. E. Koskinen, Ashwin N. Ananthakrishnan, Yang Luo, Graham Heap, Marijn C. Visschedijk, Jeffrey C. Barrett, Kim de Lange, Cathryn Edwards, AL Hart, C J Hawkey, Luke Jostins, Nicholas A. Kennedy, Christopher A Lamb, James Lee, Charlie W. Lees, John Mansfield, Christopher G. Mathew, C. Mowatt, William G. Newman, Elaine Nimmo, Miles Parkes, Martin Pollard, Natalie J. Prescott, Jessica Randall, Daniel L Rice, Jack Satsangi, Alison Simmons, Mark Tremelling, Holm H. Uhlig, David C. Wilson, Clara Abraham, J ACHKAR, Alain Bitton, Gabrielle Boucher, Kenneth Croitoru, Phil Fleshner, Jürgen Glas, Subra Kugathasan, Johan Van Limbergen, Raquel Milgrom, Deborah D. Proctor, Miguel Regueiro, L. Philip Schumm, Yashoda Sharma, Joanne M. Stempak, Stephan R. Targan, M. H. Wang, 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, Päivi Saavalainen, Kimmo Kontula, Martti Färkkilâ, Dermot McGovern, André Franke, Kāri Stefánsson, John D. Rioux, Ramnik J. Xavier, Mark J. Daly,

Ubiquitin and proteasome pathways

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.