389 A Candidate Gene Study of Rare Monogenic Disorders With IBD-Like Phenotype Identified Rare Variants in XIAP Gene in a Cohort of Early-Onset IBD Patients

Abstract

frameshift variant(rs5743293) had the strongest effect in Group6 (OR=5.52, p=1.07E-16) yet no effect in Group2(OR=1.12, p=0.78), with a p-value of 1.43E-7 for test of heterogeneity; the ATG16L1 T300A variant showed a strong effect in Group4(OR=0.589, p=1.68E-9), with weak to no effect observed in other groups(p for heterogeneity: 5.33E-5). An unbiased Immunochip-wide analysis with these subgroups compared to non-IBD controls identified a putative novel CD association with PRKCQ. Three PRKCQ SNPs contributed individually to different subgroups (rs113912197 to Group2, OR=24.47, p=8.18E-7; rs112123005 to Group3, OR=5.98, p=8.63E-6 and rs661985 to Group1, OR=1.34, p=4.70E-4). LD between these SNPs is weak(R2<0.1), suggesting they are independent signals. PRKCQ codes for nPKC-θ, a serine-protein kinase that mediates non-redundant functions in T-cell receptor signaling and plays an important role in the development of T-helper 2 cells following immune and inflammatory responses. PRKCQ is also a known locus for Rheumatoid Arthritis and Type I diabetes, making it functionally highly relevant. Conclusion: Using SOM, we identified 6 serologically-defined subgroups within CD. These subgroups have distinct clinical characteristics and different genetic load. Known CD loci also show dramatically different effects in these subgroups, indicating they are genetically more homogenous.