期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms12342
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) [DK064869, DK062432]
- National Human Genome Research Institute (NHGRI) [DK064869, DK043351, HG005923]
- Crohns and Colitis Foundation [3765]
- Leona M. AMP
- Harry B. Helmsley Charitable Trust [2015PG-IBD001]
- Amgen [2013583217]
- CCFA [3765]
- Cedars-Sinai F. Widjaja Foundation
- European Union [DK062413, AI067068, U54DE023789-01, 305479]
- Leona M. and Harry B. Helmsley Charitable Trust
- Crohn's and Colitis Foundation of America
- NIH [DK062431, U01 DK062429, U01 DK062422, R01 DK092235, U01 DK062420]
- Medical Research Council, UK [MR/J00314X/1]
- Wellcome Trust [WT091310, 098051]
- Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh
- [PO1DK046763]
- MRC [MC_UU_12010/7, G0800759, G0600329, MR/J00314X/1] Funding Source: UKRI
- Chief Scientist Office [ETM/137] Funding Source: researchfish
- Medical Research Council [MC_UU_12010/7, G0600329, G0800759, MR/J00314X/1] Funding Source: researchfish
- National Institute for Health Research [NIHR-RP-R3-12-026, ACF-2014-23-002] Funding Source: researchfish
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.
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