Recent genomic discoveries using Genome Wide Association Studies (GWAS) in both Crohn's disease (CD) and ulcerative colitis (UC) have increased our understanding of the genetic susceptibility of IBD. This novel genetic information provides important information about the various mechanisms of inflammation involved in disease pathogenesis. Targeting these various pathways with effective therapies is the key to the successful management of the IBD patient. There is, however, clear inter-individual variability in both efficacy and safety outcomes to this class of therapy which has yet to be explained. These differences may be solely explained by genetic variability as it relates to disease pathogenesis or directed to the mechanism of action of these therapies. In this application we hypothesize that therapeutic outcomes to anti-TNF( in children and young adults with IBD are associated with inter-individual genetic variability. The overall objective is to determine whether genetic loci identified by Genome Wide Association Studies (GWAS) and other genetic studies in IBD alone or in combination with clinical and/or immune markers are associated with therapeutic responsiveness to anti-TNF( therapy in pediatric IBD patients.
The specific aims i nclude:
Aim 1 : To examine the association between genetic loci identified by Genome Wide Association Studies (GWAS) and therapeutic responsiveness to anti-TNF(?therapy. Blood will be obtained from children aged <21 years of age with CD and UC for DNA sampling. We will test for the most significant GWAS IBD variants and established gene loci in the patient cohort and genotyping will be performed using high throughput genotyping techniques. Associations between genotype and primary non response to anti-TNF( therapy will be analyzed and associations between genotype and loss of response will also be determined.
Aim 2 : To determine if there are clinical and immune markers that are associated with anti-TNF( responsiveness and evaluate their interaction with identified genetic markers. Obtain blood specimens from children with CD and UC for serological immune response testing, mRNA expression of cytokines and pharmacokinetic testing. Phenotype and laboratory data at baseline and per protocol using standardized data collection forms will be collected and stored. The analyses will include testing associations and evaluate interactions of genetic, immunologic and clinical factors using multivariable statistical analyses.
Aim 3 : To develop a predictive model for responsiveness to anti-TNF( therapy in children with IBD. The novel pharmacogenetic information gained from this pilot study has the potential to not only improve the management of patients in the clinic with an existing anti-TNF( agent but also ultimately change the way we conduct large scale clinical trials, such that only patients with a higher probability of response to specific therapies will be enrolled to negate exposure to ineffective therapies and protect patients from treatment related serious and potentially fatal adverse events.
The novel pharmacogenetic information gained from this pilot study has the potential to ultimately change the way we conduct large scale clinical trials such that only patients with a higher probability of response to specific therapies will be enrolled to negate exposure to ineffective therapies and protect patients from treatment related serious and potentially fatal adverse events. The data from this study will aid in the translation of significant genetic findings into the clinical setting for IBD patients and potentially for all patients receiving anti-TNF( for other immune mediated disorders.
|Dubinsky, Marla C; Phan, Becky L; Singh, Namita et al. (2017) Pharmacokinetic Dashboard-Recommended Dosing Is Different than Standard of Care Dosing in Infliximab-Treated Pediatric IBD Patients. AAPS J 19:215-222|
|Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke et al. (2016) Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387:156-67|
|Vahabnezhad, Elaheh; Rabizadeh, Shervin; Dubinsky, Marla C (2014) A 10-year, single tertiary care center experience on the durability of infliximab in pediatric inflammatory bowel disease. Inflamm Bowel Dis 20:606-13|
|Avitzur, Yaron; Guo, Conghui; Mastropaolo, Lucas A et al. (2014) Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146:1028-39|
|Singh, Namita; Rosenthal, Casey J; Melmed, Gil Y et al. (2014) Early infliximab trough levels are associated with persistent remission in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 20:1708-13|
|Ballester, Veroushka; Guo, Xiuqing; Vendrell, Roberto et al. (2014) Association of NOD2 and IL23R with inflammatory bowel disease in Puerto Rico. PLoS One 9:e108204|
|Tong, Maomeng; Li, Xiaoxiao; Wegener Parfrey, Laura et al. (2013) A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease. PLoS One 8:e80702|
|Rabizadeh, Shervin; Dubinsky, Marla (2013) Update in pediatric inflammatory bowel disease. Rheum Dis Clin North Am 39:789-99|
|Kenny, Eimear E; Pe'er, Itsik; Karban, Amir et al. (2012) A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet 8:e1002559|
|Jostins, Luke; Ripke, Stephan; Weersma, Rinse K et al. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119-24|
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