A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
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 LLE., Ananthakrishnan AN., Luo Y., Heap GA., Visschedijk MC., UK IBD Genetics Consortium None., NIDDK IBD Genetics Consortium None., 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 DPB., 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.
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.