Association of the TNFRSF1B-rs1061622 variant with nonresponse to infliximab in ulcerative colitis

Abstract

For severe forms of ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), biological therapies, including tumor necrosis factor inhibitors (anti-TNF), are often used. However, these drugs have a high variability in treatment response. Multiple factors, such as genetic variants, can affect this variability. The goal of the study was to verify if selected candidate variants could affect response to anti-TNF in UC treatment. This association study included 76 participants suffering from UC and past or current users of anti-TNF. Clinical data for phenotyping was collected through a single visit with the participant and a medical chart review. Blood or saliva samples were collected to extract DNA and to genotype eight selected candidate variants in genes TNF, TNFAIP3, TNFRSF1 A and TNFRSF1B. For anti-TNF users, 30% of individuals were non-responders, 70% suffered from AE and none of the studied variants was associated with the response's phenotype. However, for infliximab users only (n = 44), the TNFRSF1B-rs1061622 variant was associated with nonresponse to infliximab for the first time in a cohort of UC patients (p-value = 0.028). Next steps are to replicate this association in independent cohorts and to perform functional studies to gain more evidence on the variant.

Fig. 1

Trajectory and criteria of the participants’ selection in final analyses. 137 patients were referred by the gastroenterology department of Hôpital de Chicoutimi and 107 patients were recruited. Following medical chart review, 76 patients were successfully phenotyped (all participants group) because it was found that three of the recruited patients had Crohn’s disease instead of ulcerative colitis, 24 only used vedolizumb, ustekinumab and/or tofacitinib, two were followed at a different hospital, one changed treatment solely because of anti-infliximab antibodies and one wasn’t compliant to their medication. Two people out of the 76 did not give DNA samples du to lost to follow-up of participants who had to send saliva sample by mail. For all anti-TNF combined group analyses of phenotype association, 73 patients were included because three had different phenotypes for two different anti-TNF, and 71 of these patients gave biological sample for DNA genotyping. For the infliximab subgroup phenotype analyses, 44 patients were included because the others had only taken other anti-TNFs and 43 of these patients gave biological sample for DNA genotyping.