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

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Author
Rivas, Manuel A.
Graham, Daniel
Sulem, Patrick
Stevens, Christine
Desch, A. Nicole
Goyette, Philippe
Gudbjartsson, Daniel
Jonsdottir, Ingileif
Thorsteinsdottir, Unnur
Degenhardt, Frauke
Mucha, Sören
Li, Dalin
D'Amato, Mauro
Annese, Vito
Vermeire, Severine
Weersma, Rinse K.
Halfvarson, Jonas
Paavola-Sakki, Paulina
Lappalainen, Maarit
Tukiainen, Taru
Haritunians, Talin
Halme, Leena
Koskinen, Lotta L. E.
Luo, Yang
Heap, Graham A.
Visschedijk, Marijn C.
Barrett, J
de Lange, K
Edwards, C
Hart, A
Hawkey, C
Jostins, L
Kennedy, N
Lamb, C
Lee, J
Lees, C
Mansfield, J
Mathew, C
Mowatt, C
Newman, W
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.P
Bitton, A
Boucher, G
Croitoru, K
Fleshner, P
Glas, J
Kugathasan, S
Limbergen, J.V
Milgrom, R
Proctor, D
Regueiro, M
Schumm, P.L
Sharma, Y
Stempak, J.M
Targan, S.R
Wang, M.H
Ahmad, Tariq
Anderson, Carl A.
Brant, Steven R.
Duerr, Richard H.
Silverberg, Mark S.
Cho, Judy H
Saavalainen, Päivi
Kontula, Kimmo
Färkkilä, Martti
McGovern, Dermot P. B.
Franke, Andre
Stefansson, Kari
Rioux, John D.
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. P.
Bitton, A.
Boucher, G.
Croitoru, K.
Fleshner, P.
Glas, J.
Kugathasan, S.
Limbergen, J. V.
Milgrom, R.
Proctor, D.
Regueiro, M.
Schumm, P. L.
Sharma, Y.
Stempak, J. M.
Targan, S. R.
Wang, M. H.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ncomms12342Metadata
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Rivas, M. A., D. Graham, P. Sulem, C. Stevens, A. N. Desch, P. Goyette, D. Gudbjartsson, et al. 2016. “A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.” Nature Communications 7 (1): 12342. doi:10.1038/ncomms12342. http://dx.doi.org/10.1038/ncomms12342.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980482/pdf/Terms of Use
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