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A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
- Rivas, Manuel;
- Graham, Daniel;
- Sulem, Patrick;
- Stevens, Christine;
- Desch, A;
- Goyette, Philippe;
- Gudbjartsson, Daniel;
- Jonsdottir, Ingileif;
- Thorsteinsdottir, Unnur;
- Degenhardt, Frauke;
- Mucha, Sören;
- Kurki, Mitja;
- Li, Dalin;
- DAmato, Mauro;
- Annese, Vito;
- Vermeire, Severine;
- Weersma, Rinse;
- Halfvarson, Jonas;
- Paavola-Sakki, Paulina;
- Lappalainen, Maarit;
- Lek, Monkol;
- Cummings, Beryl;
- Tukiainen, Taru;
- Haritunians, Talin;
- Halme, Leena;
- Koskinen, Lotta;
- Ananthakrishnan, Ashwin;
- Luo, Yang;
- Heap, Graham;
- Visschedijk, Marijn;
- MacArthur, Daniel;
- Neale, Benjamin;
- Ahmad, Tariq;
- Anderson, Carl;
- Brant, Steven;
- Duerr, Richard;
- Silverberg, Mark;
- Cho, Judy;
- Palotie, Aarno;
- Saavalainen, Päivi;
- Kontula, Kimmo;
- Färkkilä, Martti;
- McGovern, Dermot;
- Franke, Andre;
- Stefansson, Kari;
- Rioux, John;
- Xavier, Ramnik;
- Daly, Mark;
- 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, J;
- Bitton, A;
- Boucher, G;
- Croitoru, K;
- Fleshner, P;
- Glas, J;
- Kugathasan, S;
- Limbergen, J;
- Milgrom, R;
- Proctor, D;
- Regueiro, M;
- Schumm, P;
- Sharma, Y;
- Stempak, J;
- Targan, S;
- Wang, M
- et al.
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.
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