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