Pharmacogenetic biomarkers of response in Crohn’s disease

Abstract

Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment. Several studies have considered the possibility that these differences in response are caused by the genetic variability of patients. Many genes have been investigated as potential predictors of response to biological drugs, such as ADAM17, ATG16L1, EMSY, CASP9, CCNY, CNTN5, FASLG, FCGR, NOD2, PTGER4, IL13, IL1B, IL27, IL11, IL17F, TNF and TNFR genes. In this review, we will gather the information on influence of gene polymorphisms investigated to date on response to biological drugs in CD patients.

Is Polymorphism in the Apoptosis and Inflammatory Pathway Genes Associated With a Primary Response to Anti-TNF Therapy in Crohn’s Disease Patients?

“…Currently, much attention has been paid to the pharmacokinetics of biological drugs, which undoubtedly play a role in the long-term response. However, it seems that other mechanisms are involved in the induction phase, including genetic conditions, whereas drug pharmacokinetics is a secondary phenomenon (Drabik et al, 2016;Yamamoto-Furusho, 2017;Linares-Pineda et al, 2018). The etiopathogenesis of CD is not fully understood.…”

Genome‐wide association studies in Crohn's disease: Past, present and future

“…In addition to studying the genetic contribution to drug side effects, efforts have also been made to identify a genetic contribution to treatment response. So far, however, most of these studies have used a candidate gene approach, investigating individual genes or groups of genes – often those linked to CD susceptibility – rather than adopting a genome‐wide approach . Similar to disease susceptibility, it seems unlikely that a single variant will determine the efficacy of CD therapies, and therefore, a genome‐wide approach will be important.…”

“…So far, however, most of these studies have used a candidate gene approach, investigating individual genes or groups of genes often those linked to CD susceptibilityrather than adopting a genome-wide approach. 104 Similar to disease susceptibility, it seems unlikely that a single variant will determine the efficacy of CD therapies, and therefore, a genome-wide approach will be important. Moreover, there is no reason to suspect that variants influencing response to treatment would be the same as those that alter disease susceptibility, and thus, it was unsurprising when a polygenic risk score based on 140 CD risk loci did not associate with response to anti-TNF therapy.…”

Pre-Treatment Biomarkers of Anti-Tumour Necrosis Factor Therapy Response in Crohn’s Disease—A Systematic Review and Gene Ontology Analysis

“…Crohn’s disease (CD) is one of the two principal subtypes of Inflammatory Bowel Disease (IBD), a chronic autoimmune condition that may affect any part of the digestive system and seriously affects the quality of life [1,2,3]. The serious cases of CD/IBD are treated with biologicals, most prominently with tumour necrosis factor (TNF) inhibitors.…”

“…Genetic background and gene expression are therefore also under investigation [7,8,9,10,11,12,13]. There are several recent reviews on the topic, focusing either on clinical prediction of anti-TNF response [2,4,5,14,15] or summarizing genomic and/or expression data and proposing predictive sets of anti-TNF response markers [16,17,18,19,20]. Here, for the first time we integrate genomic and expression markers that could predict non-response to anti-TNF treatment in CD patients prior to treatment initiation into common interaction networks.…”