| Title: |
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis |
| Authors: |
Rivas, MA; Graham, D; Sulem, P; Stevens, C; Desch, AN; Goyette, P; Gudbjartsson, D; Jonsdottir, I; Thorsteinsdottir, U; Degenhardt, F; Mucha, S; Kurki, MI; Li, D; D'Amato, M; Annese, V; Vermeire, S; Weersma, RK; Halfvarson, J; Paavola-Sakki, P; Lappalainen, M; Lek, M; Cummings, B; Tukiainen, T; Haritunians, T; Halme, L; Koskinen, LL; Ananthakrishnan, AN; Luo, Y; Heap, GA; Visschedijk, MC; MacArthur, DG; Neale, BM; Ahmad, T; Anderson, CA; Brant, SR; Duerr, RH; Silverberg, MS; Cho, JH; Palotie, A; Saavalainen, P; Kontula, K; Färkkilä, M; McGovern, DP; Franke, A; Stefansson, K; Rioux, JD; Xavier, RJ; Daly, MJ; 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, JP; Bitton, A; Boucher, G; Croitoru, K; Fleshner, P; Glas, J; Kugathasan, S; Limbergen, JV; Milgrom, R; Proctor, D; Regueiro, M; Schumm, PL; Sharma, Y; Stempak, JM; Targan, SR; Wang, MH |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2017 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.1038/ncomms12342 |
| DOI: |
10.1038/ncomms12342 |
| Availability: |
https://doi.org/10.1038/ncomms12342; https://ora.ox.ac.uk/objects/uuid:8af0bfd0-c489-4ab8-be77-1a788f83e81b |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.FD5626B5 |
| Database: |
BASE |