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

Area of Science:

• Genetics
• Immunology
• Gastroenterology

Background:

• Protein-truncating variants (PTVs) can offer protection against human diseases, serving as valuable therapeutic targets.
• Inflammatory bowel disease (IBD) has known genetic associations, providing a basis for searching for protective variants.

Purpose of the Study:

• To identify PTVs conferring protection against inflammatory bowel disease (IBD).
• To validate RNF186 as a potential therapeutic target for ulcerative colitis (UC).

Main Methods:

• Targeted sequencing was employed to identify PTVs.
• Replication genotyping and imputation were used for variant analysis.
• Functional studies assessed the truncated protein's expression and localization.

Main Results:

• A PTV in RNF186 (rs36095412, p.R179X) was identified, significantly protecting against ulcerative colitis (P=6.89 × 10(-7), OR=0.30).
• The identified variant was present in up to 0.78% of the population studied (11,148 UC patients, 295,446 controls).
• The truncated RNF186 protein showed reduced expression and altered subcellular localization.

Conclusions:

• RNF186 PTVs confer protection against ulcerative colitis.
• The protective mechanism may involve loss of function due to altered protein expression, localization, or loss of a transmembrane domain.
• RNF186 is a validated therapeutic target for ulcerative colitis.