Genetic Associations with Adverse Events from Anti-TNF Therapy in IBD Patients: 2016 ACG Presidential Poster Award

Abstract

Introduction: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that includes Crohn's disease (CD) and ulcerative colitis (UC). Anti-TNF agents are effective therapies for IBD patients, but adverse events such as infusion reactions, allergic reactions, and infections limit the use of these medications. The objective of this study was to identify genetic associations with adverse events to anti-TNF agents in IBD subjects.Figure 1Methods: This study was a retrospective review of patients at Cedars-Sinai IBD Center. Patients included in the study were those that had given consent, had Immunochip data available and carried a diagnosis of IBD (Crohn's disease ulcerative colitis, or IBDU) and who had been treated with anti-TNF agents (infliximab, adalimumab, and certolizumab pegol for CD; infliximab, adalimumab, and golimumab for UC). Adverse events were identified by chart review. Standard and rigorous QC criteria were applied to the genetic data, which was generated using Immunochip. Genetic association was assessed by logistic regression after correcting for population structure. Results: Altogether we identified 1317 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 65/1317 (4.94%) subjects developed infusion reactions; 88/1317 (6.68%) subjects developed an allergic reaction; 12/1317 (0.91%) subjects developed a lupus like reaction; and 10/1317 (0.76%) developed an infection attributed to an anti-TNF. The development of any reaction was identifi ed in 187/1317 (14.2%). rs1505992 which is the known IBD SNP tagging PTGER4 was associated with allergic reaction to anti-TNF (p= 0.0054; OR 0.53). Of the known IBD-associated SNPs: rs6740462 tagging SPRED2 (p = 0.0049, OR 0.42); rs13300483 tagging TNFSF15 (p = 0.0085, OR 0.51); and rs7702331 tagging FOXD1/TMEM174 (p = 0.0089, OR 0.50) were all associated with infusion reactions. Other genetic associations with adverse events are shown in the tables. Conclusion: Our data have implicated a number of IBD-associated SNPs in adverse reactions to anti-TNF therapy in IBD subjects. In addition our data have implicated genes involved in: response to viral infection (STAT2, KIF4B); IL6 regulation (PTPN2); cAMP production (ADCY8); and endoplasmic reticulum function (SEC61B). Additional studies will be needed to replicate and extend these findings and to see if these findings together with other modalities are able to identify patients at high-risk of anti-TNF associated adverse events.