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


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.

SUBMITTER: Rivas MA 

PROVIDER: S-EPMC4980482 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Rivas Manuel A MA   Graham Daniel D   Sulem Patrick P   Stevens Christine C   Desch A Nicole AN   Goyette Philippe P   Gudbjartsson Daniel D   Jonsdottir Ingileif I   Thorsteinsdottir Unnur U   Degenhardt Frauke F   Mucha Sören S   Kurki Mitja I MI   Li Dalin D   D'Amato Mauro M   Annese Vito V   Vermeire Severine S   Weersma Rinse K RK   Halfvarson Jonas J   Paavola-Sakki Paulina P   Lappalainen Maarit M   Lek Monkol M   Cummings Beryl B   Tukiainen Taru T   Haritunians Talin T   Halme Leena L   Koskinen Lotta L E LL   Ananthakrishnan Ashwin N AN   Luo Yang Y   Heap Graham A GA   Visschedijk Marijn C MC   MacArthur Daniel G DG   Neale Benjamin M BM   Ahmad Tariq T   Anderson Carl A CA   Brant Steven R SR   Duerr Richard H RH   Silverberg Mark S MS   Cho Judy H JH   Palotie Aarno A   Saavalainen Päivi P   Kontula Kimmo K   Färkkilä Martti M   McGovern Dermot P B DP   Franke Andre A   Stefansson Kari K   Rioux John D JD   Xavier Ramnik J RJ   Daly Mark J MJ   Barrett J J   de Lane K K   Edwards C C   Hart A A   Hawkey C C   Jostins L L   Kennedy N N   Lamb C C   Lee J J   Lees C C   Mansfield J J   Mathew C C   Mowatt C C   Newman B B   Nimmo E E   Parkes M M   Pollard M M   Prescott N N   Randall J J   Rice D D   Satsangi J J   Simmons A A   Tremelling M M   Uhlig H H   Wilson D D   Abraham C C   Achkar J P JP   Bitton A A   Boucher G G   Croitoru K K   Fleshner P P   Glas J J   Kugathasan S S   Limbergen J V JV   Milgrom R R   Proctor D D   Regueiro M M   Schumm P L PL   Sharma Y Y   Stempak J M JM   Targan S R SR   Wang M H MH  

Nature communications 20160809


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  ...[more]

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