80 Increased Risk of Inflammatory Bowel Disease After Salmonella or Campylobacter Gastroenteritis: A Population-Based Cohort Study

Abstract

Background: Natural history observations in early onset IBD have prompted the increasing use of anti-TNFα therapy. Inter-individual variation, however, is seen in efficacy outcomes. These differences may be explained in part by genetic variability as it relates to disease pathogenesis or directed to the mechanism of action of these therapies. Recent GWA studies in IBD have increased our understanding of the genetic susceptibility to IBD and provide insight regarding the various mechanisms of inflammation. We hypothesize that interindividual differences in therapeutic outcomes to anti-TNFαmay be associated with IBD susceptibility genes. Aim: Test associations of GWA identified IBD susceptibility loci (34 SNPs) with infliximab (IFX) responsiveness in pediatric IBD patients. Methods: Complete follow up and GWAS data was available on 63 children receiving IFX. Harvey Bradshaw index (HBI) was used to calculate disease activity. Outcomes were primary nonresponse: no change or increase in HBI at week 10; and secondary loss of response: drop in HBI by >3 points at week 10 (response) and then increase to or above baseline HBI week 14 or later. Chi square testing examined the association between 34 SNPs and IFX responsiveness. Time to loss of response was calculated using Kaplan Meier analysis. Results: Six SNPs (Table 1) were associated with primary non-response (p < 0.05). There were 5 different SNPs (Chromosome) associated with loss of response; rs11174631 (12q12); OR =10.6, p= 0.03; rs8049439 (16p11); OR = 3.8, p= 0.03, rs2456449 (8q24); OR= 4.8, p = 0.02, rs10044354 (5q15); OR = 3.8, p = 0.03, rs6908425 (6p22); OR = 4.1, p = 0.03. Of these 5 SNPs, 4 were also associated with the time to loss of response (median 9 months): rs11174631 (p= 0.03), rs2456449 (p = 0.03), rs10044354 (p = 0.04), rs6908425 (p = 0.02). Conclusion: These findings suggest that there may be different genetic predictors and perhaps biological explanations for primary non response vs. secondary loss of response. Replication studies are currently underway. Defining predictors of response to anti-TNFα will allow the identification of patients with a high probability of response before initiating therapy so to negate exposure to ineffective therapies and protect patients from treatment related serious adverse events. Primary Non Response