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

Authors:
Manuel A Rivas, Daniel Graham, Patrick Sulem, Christine Stevens, A Nicole Desch, Philippe Goyette, Daniel Gudbjartsson, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Frauke Degenhardt, Sören 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, - -, 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 Färkkilä, Dermot P B McGovern, Andre Franke, Kari Stefansson, John D Rioux, Ramnik J Xavier, Mark J Daly, J Barrett, K de Lane, C Edwards, A Hart, C Hawkey, L Jostins, N Kennedy, C Lamb, J Lee, C Lees, J Mansfield, C Mathew, C Mowatt, B Newman, E Nimmo, M Parkes, M Pollard, N Prescott, J Randall, D Rice, J Satsangi, A Simmons, M Tremelling, H Uhlig, D Wilson, C Abraham, J P Achkar, A Bitton, G Boucher, K Croitoru, P Fleshner, J Glas, S Kugathasan, J V Limbergen, R Milgrom, D Proctor, M Regueiro, P L Schumm, Y Sharma, J M Stempak, S R Targan, M H Wang
Year of publication:
2016
Volume:
7
Issue:
-
Issn:
2041-1723
Journal title abbreviated:
NAT COMMUN
Journal title long:
Nature communications
Impact factor:
12.124
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.