A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
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DOI：
10.1038/ncomms12342
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发表时间：
2016-08-09
影响因子：
16.6
通讯作者：
Wang MH
中科院分区：
文献类型：
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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
保护人类疾病的蛋白质截断变体提供了治疗靶点的体内验证。在这里，我们使用靶向测序来搜索蛋白质截断变异，利用与相同疾病相关的常见变异的知识来保护免受炎症性肠病。通过复制基因分型和代入，我们发现预测的蛋白截断变体（rs36095412, p.R179X，在11148名溃疡性结肠炎患者和295446名对照组中进行基因分型，MAF=高达0.78%）在RNF186中具有强结肠表达的单外显子环指E3连接酶，可以预防溃疡性结肠炎（总体P=6.89 × 10−7，优势比=0.30）。我们进一步证明，截断的蛋白表现出表达减少和亚细胞定位改变，这表明保护机制可能存在于通过错定位和/或基本跨膜结构域的丧失而失去相互作用或功能。虽然数百个基因座与炎症性肠病（IBDs）有关，但相关变异的功能后果尚不清楚。在这里，作者在溃疡性结肠炎（UC）患者的基因组中筛选IBD位点附近的蛋白质截断变异体，并在RNF186中发现一种蛋白质截断变异体对UC具有保护作用。
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. While hundreds of loci are linked with inflammatory bowel diseases (IBDs), the functional consequences of the associated variants remain unclear. Here, the authors screened in ulcerative colitis (UC) patients' genomes for protein-truncating variants near IBD loci, and identify a protein truncating variant in RNF186 to be protective against UC.