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

Nat Commun
Authors
Manuel Rivas
Daniel Graham
Patrick Sulem
Christine Stevens
A Nicole Desch
Philippe Goyette
Daniel Gudbjartsson
Ingileif Jonsdottir
Unnur Thorsteinsdottir
Frauke Degenhardt
Sören Mucha
Mitja Kurki
Dalin Li
Mauro D'Amato
Vito Annese
Severine Vermeire
Rinse Weersma
Jonas Halfvarson
Paulina Paavola-Sakki
Maarit Lappalainen
Monkol Lek
Beryl Cummings
Taru Tukiainen
Talin Haritunians
Leena Halme
Lotta Koskinen
Ashwin Ananthakrishnan
Yang Luo
Graham Heap
Marijn Visschedijk
UK IBD Genetics Consortium
NIDDK IBD Genetics Consortium
Daniel MacArthur
Benjamin Neale
Tariq Ahmad
Carl Anderson
Steven Brant
Richard Duerr
Mark Silverberg
Judy Cho
Aarno Palotie
Päivi Saavalainen
Kimmo Kontula
Martti Färkkilä
Dermot McGovern
Andre Franke
Kari Stefansson
John Rioux
Ramnik Xavier
Mark Daly
Barrett
K de Lane
C Edwards
A Hart
C Hawkey
Jostins
N Kennedy
C Lamb
Lee
C Lees
Mansfield
C Mathew
C Mowatt
B Newman
E Nimmo
Parkes
M Pollard
N Prescott
J Randall
D Rice
Satsangi
Simmons
M Tremelling
H Uhlig
Wilson
C Abraham
J Achkar
Bitton
Boucher
K Croitoru
Fleshner
J Glas
Kugathasan
J Limbergen
Milgrom
D Proctor
M Regueiro
P Schumm
Sharma
J Stempak
S Targan
M Wang
Abstract

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.
Year of Publication
2016
Journal
Nat Commun
Volume
7
Pages
12342
Date Published
2016 Aug 09
ISSN
2041-1723
DOI
10.1038/ncomms12342
PubMed ID
27503255
PubMed Central ID
PMC4980482
Links
Grant list
U54 DE023789 / DE / NIDCR NIH HHS / United States
U01 DK062413 / DK / NIDDK NIH HHS / United States
U01 HG005923 / HG / NHGRI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States
R01 DK064869 / DK / NIDDK NIH HHS / United States
U01 DK062429 / DK / NIDDK NIH HHS / United States
U01 DK062422 / DK / NIDDK NIH HHS / United States
MR/J00314X/1 / Medical Research Council / United Kingdom
U01 AI067068 / AI / NIAID NIH HHS / United States
P01 DK046763 / DK / NIDDK NIH HHS / United States
U01 DK062420 / DK / NIDDK NIH HHS / United States
U01 DK062431 / DK / NIDDK NIH HHS / United States
R01 DK092235 / DK / NIDDK NIH HHS / United States

Recent Ó³»­´«Ã½ Publications