The Unsolved Link of Genetic Markers and Crohn's Disease Progression: A North American Cohort Experience

• Published in: Inflammatory bowel diseases Vol. 25; no. 9; pp. 1541 - 1549
• Main Authors: O'Donnell, Sarah, Borowski, Krzysztof, Espin-Garcia, Osvaldo, Milgrom, Raquel, Kabakchiev, Boyko, Stempak, Joanne, Panikkath, Deepah, Eksteen, Bertus, Xu, Wei, Steinhart, A Hillary, Kaplan, Gilaad G, McGovern, Dermot P B, Silverberg, Mark S
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.09.2019
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Analysis; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Crohn Disease - genetics; Crohn Disease - pathology; Crohn Disease - surgery; Development and progression; Disease Progression; Disease susceptibility; Female; Follow-Up Studies; Genetic aspects; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Genomics; Humans; Male; Medical research; Medicine, Experimental; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Prognosis; Single nucleotide polymorphisms; Survival Rate; Time-to-Treatment; Young Adult; Canada; genetics; genome-wide association; prognosis; Crohn’s disease
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1093/ibd/izz016

While progress has been made in the identification of Crohn's disease (CD) susceptibility loci, efforts to identify a genetic basis for disease progression have been less fruitful. The specific aim of this study was to build upon the major genetic advances made in IBD by applying genome-wide technologies toward predicting disease progression in CD. Crohn's disease cases (n = 1495) from 3 IBD centers were reviewed by experienced physicians. Clinical and demographic details were collected, focusing on the time to first disease progression. Genome-wide association (GWA) analysis was carried out on 3 clinical outcomes: 1) time to disease progression; 2) time to first abdominal surgery; and 3) a binary analysis of indolent vs progressive disease. Cox-proportional hazard and logistic regression models were used. A GWA analysis was carried out to determine any genetic variation associated with the time to disease progression; 662 cases were included after quality control (QC) and exclusion of any cases with B2/B3 behavior at baseline (n = 450). There were 1360 cases included after QC in the time to abdominal surgery analysis. No variant reached genome-wide significance in any of the 3 analyses performed. Eight known IBD susceptibility single nucleotide polymorphism (SNPs) were found to be associated with time-to-abdominal surgery SMAD3 (rs17293632), CCR6 (rs1819333), CNTF (rs11229555), TSPAN14 (rs7097656), CARD9 (rs10781499), IPMK (rs2790216), IL10 (rs3024505), and SMURF1 (rs9297145) (P < 0.05). Our GWA study failed to show any SNP-phenotype association reaching genome-wide significance. It is likely that multiple variables affect disease progression, with genetic factors potentially having only a small effect size.