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* = Presenting author

P699 Genetic and clinical characterization of 56 multiple-affected IBD families

A. Settesoldi*1, M. Vancamelbeke2, T. Billiet2, V. Ballet3, S. Singh4, S. Lockton4, F. Princen4, G. Van Assche3, P. Rutgeerts3, S. Vermeire3, I. Cleynen2

1AOU Careggi, Gastroenterology, Florence, Italy, 2Department of Clinical and Experimental Medicine, KU Leuven, Translational Research in GastroIntestinal Disorders, Leuven, Belgium, 3UZ Leuven, Gastroenterology, Leuven, Belgium, 4Prometheus Therapeutics & diagnostics, Prometheus Laboratories Inc, San Diego, California, United States

Background

Inflammatory bowel disease (IBD) pathogenesis comprises genetic, environmental and immunological factors. 163 genetic loci have been associated with the risk of IBD. Multiple-affected families (≥ 3 first-degree relatives affected) may have a higher genetic risk burden. We characterized these families clinically and genetically to find to what extent the 163 loci are associated with IBD in these families.

Methods

We included 62 multiplex families affected by Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U). We collected demographic (sex, smoking) and clinical data (age at diagnosis, disease location and behavior). We genotyped affected and unaffected members with Immunochip for the 163 loci. We analyzed serum samples for the Prometheus serology panel (ASCAA, ASCAG, CBir1, Fla2, FlaX, OmpC, ANCA).

Results

Among our families, 39 were CD, 2 UC, 17 CD/UC and 4 CD/IBD-U. They comprised in total 190 CD, 38 UC, 6 IBD-U and 307 healthy relatives. The average age at diagnosis was 25 years for CD (IQR 20-34) and 31 for UC (IQR 26-39). CD members of a same family showed high concordance in smoking habit (72%), age at diagnosis (87%), disease location (74%) and behavior (69%). The difference in average number of risk alleles (RA) between affected and unaffected members was not significant, nor between affected members and 2612 unrelated cases. Quartile analysis of the number of risk alleles showed that patients were most represented in Q4 and unaffected in Q1 (p=2.61x10-03). Of the 163 loci, 18 SNPs were nominally significant for the parenTDT test. The most significant (p=2.08x10-03) was rs2155219, located in 11q13 between C11orf30 and LRRC32. NOD2 frameshift mutation was also significantly associated with Crohn's disease (p=0.045). We found no enrichment of particular disease-associated pathways in any of the families. The serology panel was disease-dependent rather than family-dependent, with low intraclass correlation coefficients within families (0.06-0.21), suggesting that these antibodies increase with inflammation. Sensitivity, specificity, PPV and NPV for a diagnostic prediction of IBD vs non-IBD were 85.6%, 75.9%, 85% and 76.8%, respectively.

Conclusion

This is the largest cohort of multiple-affected IBD families studied to date. We found a high degree of concordance among CD patients of a same family in clinical features. We found nominal significance for disease association with 18 of the known IBD susceptibility loci but they do not explain much of genetic risk in these families. Exome sequencing on families with a low genetic risk score could identify additional risk loci. Serology markers could be useful to diagnose disease rather than to predict it.