Su1757 Genetic Risk Profiling Alone or in Combination With Serum Anti-Microbial Antibodies for the Stratification of Complicated Crohn's Disease Courses

Abstract

Background: The disease course in Crohn's disease (CD) is highly heterogeneous, with the majority of patients developing complications over time, such as strictures and fistulae, requiring surgical intervention. Tools to stratify patients could improve patient care and allow targeted therapeutic approaches. Several genetic variants, including NOD2/CARD15, have been linked to complicated CD courses. Aims: Exploratory cross sectional analysis for an association of genetic variants and serology in CD patients with the occurrence of complications, need for surgery and early disease onset. Methods: 323 CD patients (mean age at diagnosis: 28.5±11.8 years, mean age at sample procurement 35.7±11.9 years, 52.9% female) from a German referral center were genotyped for 94 IBD associated polymorphisms (Wellcome Trust Case Control Consortium investigation (Nature 2007, 447(7145):661-78)). The serum anti-glycan antibodies gASCA, AMCA, ACCA, ALCA, Anti-L and Anti-C were measured by ELISA. Complete clinical information was recorded in a prospectively maintained database, including complications, surgery, disease location and early age at disease onset (defined as ,40 years). Results: During the median follow-up time of 8.3 years (interquartile range (IQR) 4.6 14) 79.3% of the patients developed complications, 74.3% underwent surgery and 86.7% had early disease onset. After adjusting for ileal disease location and age of disease onset and using a dominant genetic model 5 genetic variants were associated with complications (FAF1 RS11205760, IL10C592A RS1800872, NOD2 SNP12 RS2066845, 3' UTR FAF1 RS2484676, UTR near AGTR1 RS1462651; OR range 1.8 6.25, p,0.05), 4 were linked to need for surgery (FAF1 RS11205760, MDR1 RS3789243, MPP1 RS2048294, 3' UTR FAF1 RS2484676; OR range 1.8 2.2, p ,0.05) and 4 to early disease onset (CYLD RS17223195, HERC2 RS916977, STAT3 RS744166, TJP2 RS3750551; OR range 2.1 2.4, p,0.05). NOD2 SNP12 (RS2066845) was the overall strongest determinant of complicated CD (OR 6.26 (95% CI 1.16, 33.3). When adding the above genetic variants to positivity for at least two anti-glycan antibodies the discriminatory capability (area under the curve) increased for complication versus no complication for FAF1 RS11205760, IL10C592A RS1800872 and UTR near AGTR1 RS1462651 (p,0.05), increased for surgery versus no surgery for FAF1 RS11205760, MDR1 RS3789243 and 3' UTR FAF1 RS2484676 (p,0.05), but did not increase for early disease onset. Conclusion: IBD associated susceptibility genes may increase the risk for complicated CD, need for surgery and early disease onset and could enhance the accuracy of anti-glycan antibodies. We are currently developing a risk prediction model including clinical predictors, anti-glycan antibodies and the abovementioned genotypes for patients at risk for complicated CD courses.