Genetic Predictors of Crohnʼs Disease of the Ileal Pouch Anal Anastomosis: 2011 ACG IBD Award

Abstract

Purpose: Ileal-pouch anal anastomosis (IPAA) is the surgical treatment of choice for patients with ulcerative colitis (UC) and indeterminate colitis who require surgery. A subsequent change in diagnosis to Crohn's disease (CD) involving the IPAA is an uncommon but increasingly recognized complication of this surgery and can be associated with risk of pouch loss. Based on increasing knowledge of genetic susceptibility in CD and UC, our aim was to determine if genetic factors are associated with risk of being diagnosed with CD of IPAA. Methods: A total of 837 subjects from a DNA bank met inclusion criteria: 97 subjects with CD of IPAA, 470 with “typical” CD and 270 with UC. CD of IPAA was diagnosed on the basis of one or more of the following: 1) colectomy pathology consistent with CD, 2) evidence of ulcers or strictures in the ileum proximal to the pouch in the absence of NSAID use, 3) development of perianal or abdominal fistulizing disease more than 1 year after IPAA surgery. Genotyping for single nucleotide polymorphisms (SNPs) in NOD2 (SNPs 8, 12 and 13), ATG16L1, IRGM, IL23R, and PTPN2 was performed using TaqMan assays. Results: There were baseline differences between the three groups with UC subjects having a higher proportion of male gender, a lower rate of current smoking, and a lower rate of family history of IBD (Table 1). Differences in variant allele frequency across the 3 groups were seen for IL23R, ATG16L1 and NOD2 SNPs but ATG16L1 appeared to best distinguish CD of IPAA from UC subjects. Multivariable baseline-category logit regression analysis was performed to assess associations between ATG16L1, smoking history and family history with CD of IPAA disease status versus UC and CD separately. The ATG16L1 G allele variant (OR = 1.4; P = 0.05) and current smoking (OR = 6.8; P < 0.001) were associated with increased risk of CD of IPAA compared to UC whereas no differences were seen between CD of IPAA versus CD. For each ATG16L1 G allele, subjects were 40% more likely to have CD of IPAA versus UC after adjusting for smoking and family history.Table 1: Demographic features and genotype resultsConclusion: The ATG16L1 variant is associated with increased risk of CD of IPAA. However, since this variant also occurs commonly in UC, its use in predicting subsequent diagnosis of CD at time of surgery for UC is limited. Current smoking, a modifiable risk factor, is strongly associated with CD of IPAA.Table 2: Logistic regression model: Crohn's of the Pouch vs, ulcerative colitis