J Crohns Colitis. 2024 Aug 14;18(8):1190-1201. doi: 10.1093/ecco-jcc/jjad133.

Simeng Lin ^1 2, Eilis Hannon ³, Mark Reppell ⁴, Jeffrey F Waring ⁴, Nizar Smaoui ⁴, Valerie Pivorunas ⁴, Heath Guay ⁴, Neil Chanchlani ^1 2, Claire Bewshea ², Benjamin Y H Bai ^5 6, Nicholas A Kennedy ^1 2, James R Goodhand ^1 2, Jonathan Mill ³, Tariq Ahmad ^1 2

Author information

¹Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.

²Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.

³University of Exeter Medical School, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.

⁴Precision Medicine Immunology, AbbVie Inc., Chicago, IL, USA.

⁵Genomics of Inflammation and Immunity Group, Wellcome Sanger Institute, Hinxton, UK.

⁶Postgraduate School of Life Sciences, University of Cambridge, Cambridge, UK.

Abstract

Background and aims: Anti-tumour necrosis factor [TNF] treatment failure in patients with inflammatory bowel disease [IBD] is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14.

Methods: DNA methylation from 1104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease [PANTS] study were assessed using the Illumina EPIC Beadchip [v1.0] at baseline and weeks 14, 30, and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 if they were assessed at subsequent time points and were not in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 94], with patients who responded at week 14 and when assessed at subsequent time points were in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 93].

Results: Overall, between baseline and week 14, we observed 4999 differentially methylated positions [DMPs] annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses. Epigenome-wide association [EWAS] analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at Week 14. Of these, 125 DMPs demonstrated shared associations with other common traits [proportion of shared CpGs compared with DMPs] including body mass index [23.2%], followed by C-reactive protein [CRP] [11.5%], smoking [7.4%], alcohol consumption per day [7.1%], and IBD type [6.8%]. EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients [Spearman's rho = -0.94, p <0.001].

Conclusion: Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy.