Differential Effect of Genetic Burden on Disease Phenotypes in Crohn's Disease and Ulcerative Colitis in a Canadian Cohort

Jack X Q Pang; Hengameh Kheirkhahrahimabadi; Sunint Bindra; Gurmeet Bindra; Remo Panaccione; Bertus Eksteen; Gilaad G Kaplan; Yasmin Nasser; Paul L Beck; Humberto B Jijon

doi:10.1093/jcag/gwaa002

Differential Effect of Genetic Burden on Disease Phenotypes in Crohn's Disease and Ulcerative Colitis in a Canadian Cohort

J Can Assoc Gastroenterol. 2020 Feb 3;4(2):65-72. doi: 10.1093/jcag/gwaa002. eCollection 2021 Apr.

Affiliations

¹ Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
² Current Address: Aspen Woods Clinic, Calgary, Alberta, Canada.

Abstract

Background and aims: Crohn's disease (CD) and ulcerative colitis (UC) demonstrate considerable phenotypic heterogeneity and course. Accurate predictors of disease behaviour are lacking. The contribution of genetics and specific polymorphisms is widely appreciated; however, their cumulative effect(s) upon disease behaviour remains poorly understood. Here, we investigate the relationship between genetic burden and disease phenotype in a Canadian inflammatory bowel disease (IBD) Cohort.

Methods: We retrospectively examined a cohort of CD and UC patients recruited from a single tertiary referral center genotyped using a Goldengate Illumina platform. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for 151 IBD-risk loci was calculated and evaluated for phenotypic associations.

Results: Among CD patients, higher GRS was associated with earlier onset of disease (regression coefficient -2.19, 95% confidence interval [CI] -3.77 to -0.61, P = 0.007), ileal disease (odds ratio [OR] 1.45), stricturing/penetrating disease (OR 1.72), perianal disease (OR 1.57) and bowel resection (OR 1.66). Higher GRS was associated with use of anti-tumor necrosis factor (TNF) (P < 0.05) but not immunomodulators. Interestingly, we could not demonstrate an association between higher GRS and family history of IBD (OR 1.27, P = 0.07). Onset of disease remained statistically significant for never smokers (P = 0.03) but not ever smokers (P = 0.13). For UC, having a higher GRS did not predict the age of diagnosis nor was it predictive of UC disease extent (P = 0.18), the need for surgery (P = 0.74), nor medication use (immunomodulators P = 0.53, anti-TNF P = 0.49). We could not demonstrate an association between increased GRS and having a family history of IBD in the UC group.

Conclusions: Increasing genetic burden is associated with early age of diagnosis in CD and may be useful in predicting disease behaviour in CD but not UC.

Keywords: Age at diagnosis; Crohn’s disease; Genetic burden; Ileal disease; Phenotype.