Validation of epigenetic markers for prediction of response to topical corticosteroid treatment in eosinophilic esophagitis

Abstract

Background: We previously identified 18 CpG methylation biomarkers associated with treatment response to topical steroids (tCS) in eosinophilic esophagitis (EoE). Here, in an independent cohort, we assessed the validity of these CpG sites as treatment response biomarkers. Methods: DNA was extracted from prospectively biobanked esophageal biopsies from newly diagnosed EoE patients enrolled in a randomized trial of two tCS formulations. Histologic response was defined as <15 eosinophils per high-power field (eos/hpf). Pre-treatment DNA methylation was assayed on the Illumina Human MethylationEPIC BeadChip. Logistic regression and area under the ROC (AUC) analyses, adjusting for chip, position on the chip, age, sex, and baseline eosinophil count, were computed to test for an association between DNA methylation and treatment response at the 18 previously identified CpG sites. Results: We analyzed 88 patients (58 histologic responders, 30 non-responders), with a mean age of 38±16 years, 64% male, 97% White race. Of the 18 CpG sites, 13 met quality control criteria, and three were associated with responder status (p<0.012), including sites within UNC5B (cg26152017), ITGA6 (cg01044293), and LRRC8A (cg13962589). All three showed evidence of reduced methylation in treatment responders, consistent with the original discovery associations. The predictive probability for non-response with all three CpG sites was strong (AUC=0.79). Discussion: We validated epigenetic biomarkers (CpG methylation sites) for prediction of tCS response in EoE patients in an independent population. While not all previously identified markers replicated, three demonstrated a relatively high predictive probability for response to treatment and hold promise for guiding tCS treatment in EoE.