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

• Published in: bioRxiv
• Main Authors: Rivas, Manuel A, Graham, Daniel, Sulem, Patrick, Stevens, Christine, Desch, Nicole, Goyette, Philippe, Gudbjartsson, Daniel, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Degenhardt, Frauke, Mucha, Soren, Kurki, Mitja I, Li, Dalin, D'amato, Mauro, Annese, Vito, Vermeire, Severine, Weersma, Rinse, Halfvarsson, Jonas, Paavola-Sakki, Paulina, Lappalainen, Maarit, Lek, Monkol, Cummings, Beryl, Tukianen, Taru, Haritunians, Talin, Halme, Leena, Koskinen, Lotta, Ananthakrishnan, Ashwin, Luo, Yang, Heap, Graham A, Visschedijk, Marijn, Niddk Ibd Genetics Consortium, Uk Ibd Genetics Consortium, Macarthur, Daniel G, Neale, Benjamin M, Ahmad, Tariq, Anderson, Carl A, Brant, Steven R, Duerr, Richard H, Silverberg, Mark, Cho, Judy, Palotie, Aarno, Saavalainen, Paivi, Kontula, Kimmo, Farkkila, Martti, Mcgovern, Dermot, Franke, Andre, Stefansson, Kari, Rioux, John D, Xavier, Ramnik J, Daly, Mark J
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 23.12.2015
• Subjects: Colon; Inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Proteins; Ubiquitin-protein ligase; Ulcerative colitis
• DOI: 10.1101/035105

We conducted a search for protein truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. We found that a 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 (OR) = 0.30). We further demonstrate that the truncated protein is expressed, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization or loss of an essential protein element.