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

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Rivas , M A , Graham , D , Sulem , P , Stevens , C , Desch , A N , Goyette , P , Gudbjartsson , D , Jonsdottir , I , Thorsteinsdottir , U , Degenhardt , F , Mucha , S , Kurki , M I , Li , D , D'Amato , M , Annese , V , Vermeire , S , Weersma , R K , Halfvarson , J , Paavola-Sakki , A L P , Lappalainen , A M , Lek , M , Cummings , B , Tukiainen , T , Haritunians , T , Halme , L , Koskinen , L L E , Ananthakrishnan , A N , Luo , Y , Heap , G A , Visschedijk , M C , MacArthur , D G , Neale , B M , Ahmad , T , Anderson , C A , Brant , S R , Duerr , R H , Silverberg , M S , Cho , J H , Palotie , A , Saavalainen , P , Kontula , K , Farkkila , M , McGovern , D P B , Franke , A , Stefansson , K , Rioux , J D , Xavier , R J & Daly , M J 2016 , ' A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis ' , Nature Communications , vol. 7 , 12342 . https://doi.org/10.1038/ncomms12342

Title: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Author: Rivas, Manuel A.; Graham, Daniel; Sulem, Patrick; Stevens, Christine; Desch, A. Nicole; Goyette, Philippe; Gudbjartsson, Daniel; Jonsdottir, Ingileif; Thorsteinsdottir, Unnur; Degenhardt, Frauke; Mucha, Soeren; Kurki, Mitja I.; Li, Dalin; D'Amato, Mauro; Annese, Vito; Vermeire, Severine; Weersma, Rinse K.; Halfvarson, Jonas; Paavola-Sakki, Anu Liisa Paulina; Lappalainen, Anne Maarit; Lek, Monkol; Cummings, Beryl; Tukiainen, Taru; Haritunians, Talin; Halme, Leena; Koskinen, Lotta L. E.; Ananthakrishnan, Ashwin N.; Luo, Yang; Heap, Graham A.; Visschedijk, Marijn C.; MacArthur, Daniel G.; Neale, Benjamin M.; Ahmad, Tariq; Anderson, Carl A.; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Cho, Judy H.; Palotie, Aarno; Saavalainen, Paivi; Kontula, Kimmo; Farkkila, Martti; McGovern, Dermot P. B.; Franke, Andre; Stefansson, Kari; Rioux, John D.; Xavier, Ramnik J.; Daly, Mark J.
Contributor organization: Department of Medicine
Gastroenterologian yksikkö
Immunobiology Research Program
Research Programs Unit
Department of Medical and Clinical Genetics
II kirurgian klinikka
Department of Surgery
Institute for Molecular Medicine Finland
Aarno Palotie / Principal Investigator
Kimmo Kontula Research Group
Genomics of Neurological and Neuropsychiatric Disorders
Date: 2016-08
Language: eng
Number of pages: 7
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/ncomms12342
URI: http://hdl.handle.net/10138/167006
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 x 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.
3111 Biomedicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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