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

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 Soeren; 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

来源：Nature Communications, 2016, 7(1): 12342.

DOI：10.1038/ncomms12342

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.

• 出版日期2016-8