A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
Manuel A RivasDaniel GrahamPatrick SulemChristine StevensA Nicole DeschPhilippe GoyetteDaníel F GuðbjartssonIngileif JonsdottirUnnur ThorsteinsdottirFrauke DegenhardtSören MuchaMitja I KurkiDalin LiMauro D'AmatoVito AnneseSeverine VermeireRinse K WeersmaJonas HalfvarsonPaulina Paavola-SakkiMaarit LappalainenMonkol LekBeryl CummingsTaru TukiainenTalin HarituniansLeena HalmeLotta L E KoskinenAshwin N AnanthakrishnanYang LuoGraham A HeapMarijn C Visschedijknull nullnull nullDaniel G MacArthurBenjamin M NealeTariq AhmadCarl A AndersonSteven R BrantRichard H DuerrMark S SilverbergJudy H ChoAarno PalotiePäivi SaavalainenKimmo KontulaMartti FärkkiläDermot P B McGovernAndre FrankeKari StefanssonJohn D RiouxRamnik J XavierMark J DalyJ BarrettK de LaneC EdwardsA HartC HawkeyL JostinsN KennedyC LambJ LeeC LeesJ MansfieldC MathewC MowattB NewmanE NimmoM ParkesM PollardN PrescottJ RandallD RiceJ SatsangiA SimmonsM TremellingH UhligD WilsonC AbrahamJ P AchkarA BittonG BoucherK CroitoruP FleshnerJ GlasS KugathasanJ V LimbergenR MilgromD ProctorM RegueiroP L SchummY SharmaJ M StempakS R TarganM H WangPublished in: Nature communications (2016)
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.