Erratum: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
Erratum: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
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DOI：
10.1038/ncomms12869
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发表时间：
2016-09-13
影响因子：
16.6
通讯作者：
Daly, Mark J.
中科院分区：
文献类型：
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作者：
Rivas, Manuel A.;Graham, Daniel;Sulem, Patrick;Stevens, Christine;Desch, A. 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 K.;Halfvarson, Jonas;Paavola-Sakki, Paulina;Lappalainen, 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.
针对人类疾病的蛋白质截短变体提供了治疗靶标的体内验证。在这里，我们利用与同一疾病相关的常见变异的知识，使用靶向测序来搜索能够预防炎症性肠病的蛋白质截短变异。通过复制基因分型和插补，我们发现RNF186（一种具有强结肠表达的单外显子环指E3连接酶）中预测的蛋白质截短变异（rs36095412，p.R179X，在11,148名溃疡性结肠炎患者和295,446名对照者中进行基因分型，MAF=高达0.78%）可预防溃疡性结肠炎 （总体 P=6.89 × 10−7，优势比=0.30）。我们进一步证明，截短的蛋白质表现出表达减少和亚细胞定位改变，这表明保护机制可能在于通过错误定位和/或重要跨膜结构域的丢失而导致相互作用或功能的丧失。
Protein-truncating variants protective against human disease providein vivovalidation 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%) inRNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overallP=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.
影响因子：
16.6
作者：
Rivas MA;Graham D;Sulem P;Stevens C;Desch AN;Goyette P;Gudbjartsson D;Jonsdottir I;Thorsteinsdottir U;Degenhardt F;Mucha S;Kurki MI;Li D;D'Amato M;Annese V;Vermeire S;Weersma RK;Halfvarson J;Paavola-Sakki P;Lappalainen M;Lek M;Cummings B;Tukiainen T;Haritunians T;Halme L;Koskinen LL;Ananthakrishnan AN;Luo Y;Heap GA;Visschedijk MC;UK IBD Genetics Consortium;NIDDK IBD Genetics Consortium;MacArthur DG;Neale BM;Ahmad T;Anderson CA;Brant SR;Duerr RH;Silverberg MS;Cho JH;Palotie A;Saavalainen P;Kontula K;Färkkilä M;McGovern DP;Franke A;Stefansson K;Rioux JD;Xavier RJ;Daly MJ;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 JP;Bitton A;Boucher G;Croitoru K;Fleshner P;Glas J;Kugathasan S;Limbergen JV;Milgrom R;Proctor D;Regueiro M;Schumm PL;Sharma Y;Stempak JM;Targan SR;Wang MH
通讯作者：
Wang MH