Whole-exome sequencing for inflammatory bowel disease patients treated with biologic agents

• Applicant: Professor David Ellinghaus, Ph.D.
• Subject Area: Human Genetics ; Epidemiology and Medical Biometry/Statistics ; Gastroenterology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458902672

Inflammatory bowel diseases (IBD) represent a group of relapsing-remitting and so far uncurable immune-mediated disorders, characterized by inflammation and ulceration of the entire gastrointestinal tract. Moderate to severe forms of IBD are often treated with biologic agents, mainly tumor necrosis factor (TNF) inhibitors (e.g. infliximab or adalimumab). Recently, an international multi-center clinical study showed that vedolizumab is superior to adalimumab in achieving clinical remission; however, only in a maximum of 32% of IBD patients clinical remission was achieved by biologic therapy.Although genome-wide association studies (GWAS) of the past 10 years have deepened our understanding of IBD pathogenesis through identification of disease-associated genetic variants, the use of these identified variants as markers for personalized medicine (PM) is limited in IBD. We hypothesize that the identification of protein-coding variants associated with response to therapy with biologic agents has enormous potential to contribute to the development of novel PM approaches in the management of IBD. As a proof-of-principle study, my colleagues and I recently performed a whole-exome-sequencing (WES) study for a total of 139 Korean and 77 German anti-TNF naïve IBD patients who received infliximab as a therapy. We identified five protein-coding variants that were associated with primary nonresponse (PNR) to infliximab, with rs2228273 in ZNF133 associated in both Korean and German cohorts (P=6.49×10-7; OR [95% CI] = 11.94 [3.8-37.4]). Further, the performance of a combined PNR prediction model including genetic and clinical variables was superior to the model including only genetic variables or only clinical variables.With this application, we apply for funding for whole-exome-sequencing (WES) experiments for 773 IBD patients from studies RUNcd (head-to-head comparison ustekinumab/TNF inhibitors) and VEDOibd (head-to-head comparison vedolizumab/TNF inhibitors) in order to investigate the functional genetic basis of the response/non-response to IL12/IL23 (ustekinumab), α4β7-Integrin (vedolizumab) and TNF (infliximab or adalimumab) inhibition. WES data of these 773 IBD patients will be combined with existing WES data from additional 1,219 IBD patients from the BioCrohn (head-to-head comparison infliximab/adalimumab) and the BioColitis (head-to-head comparison infliximab/adalimumab) register. We aim to identify genetic markers that support the individual prediction of the expected response to treatment and to characterize in detail the (possibly sex-specific) functional genetic basis of response with biologic agents ustekinumab, vedolizumab and infliximab/adalimumab as well as possible causal relationships between response and treatment-emergent comorbid events.

• DFG Programme: Research Grants