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8. Characterization of the ∼40,000 patient cohort of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC)

C.W. Lees1, International IBD Genetics Consortium, 1Western General Hospital, Gastrointestinal Unit, Edinburgh, United Kingdom

Background

The IIBDGC consists of multiple collaborating groups that have assembled the largest IBD bioresource to date. The Consortium's most recent genetic study was performed on over 75,000 individuals, expanding the number of known IBD loci to more than 160. To date, large-scale genetic studies have concentrated on the broad phenotypes of CD and UC, while smaller studies suggest molecular associations may explain the heterogeneity observed in clinical presentation. This enormous IBD resource provides an opportunity to evaluate a number of clinically important phenotypic variables and their relation to genetic variation.

Methods

Guidelines for core sub-phenotypes were distributed to all IIBDGC members. Clinical data on a total of 18,824 CD and 15,382 UC have been collected and collated including gender, age at diagnosis, CD location and behaviour, UC disease extent, duration of follow-up, surgical history and smoking status. QC analyses were used to identify non-random patterns of missing data and potential differences in classification. Preliminary genotype-phenotype analyses have been performed using the immunochip release 5 dataset, which contains QC'd data on 157,020 variants. Association analysis was performed using PLINK, with inclusion of the first 6 principal components as covariates to account for population stratification.

Results

The median age at diagnosis for CD was 23y (IQR 16–33), compared to 30y (21–43) for UC. 30% of CD patients had ileal disease (L1, n = 4237), 25% colonic (L2, n = 3555), and 45% ileocolonic (L3, n = 6283). 25% of CD patients had stricturing (B2, n = 3373) and 24% penetrating (B3, n = 3220) disease. 28% (n = 3481) of patients had perianal CD. The prevalence of surgery in CD was 53% (range 36–57% between sites). In UC, 13% of patients had proctitis (E1, n = 1457), 36% left-sided (E2, n = 4036), and 51% extensive disease (E3, n = 5707). Genotype-phenotype analyses confirmed a strong association between the NOD2 locus and ileal versus non-ileal CD (p = 8.92×10−24, OR = 1.50 [IQR 1.39–1.63]), and also showed an association of the MHC/HLA region with ileal disease (p = 1.27×10−15, OR = 0.64 [0.57–0.71]) and with extensive versus non-extensive UC (p = 5.78×10−13, OR = 1.50[1.34–1.67]).

Conclusion

These findings provide a robust platform for more detailed genotype-phenotype analysis which will enhance our understanding of the underlying pathogenesis of sub-groups within IBD. This is an important step towards an individualized approach to IBD management and improved patient outcomes.