Whole blood DNA methylation changes are associated with anti-TNF drug concentration in patients with Crohn's disease

Abstract

Background and Aims Anti-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 1,104 whole blood samples from the Personalised Anti-TNF Therapy in Crohn's disease (PANTS) study were assessed using the Illumina EPIC Beadchip at baseline, weeks 14, 30 and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 and were not in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 94) with patients who responded at week 14 and were in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 93). Results Overall, between baseline and week 14, we observed 4,999 differentially methylated probes (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 to DMPs) including body mass index (23.2%), followed by 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.

Competing Interest Statement

Simeng Lin reports non-financial support from Pfizer outside the submitted work. Mark Reppell, Jeffrey F Waring, Valerie Pivorunas, Nizar Smaoui, Heath Guay are employees of AbbVie and may own stock/options. Nicholas A. Kennedy reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV and non-financial support from Immundiagnostik; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, and personal fees and non-financial support from Dr Falk, outside the submitted work. James R. Goodhand reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV and non-financial support from Immundiagnostik outside the conduct of the study. Tariq Ahmad reports grants and non-financial support from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV and non-financial support from Immundiagnostik; personal fees from Biogen inc, grants and personal fees from Celltrion Healthcare, personal fees and non-financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech and non-financial support from Tillotts, outside the submitted work. Eilis Hannon, Claire Bewshea, Neil Chanchlani and Jonathan Mill declare no competing interests.

Funding Statement

PANTS is an investigator-led study funded by CORE (renamed Guts UK in 2018), the research charity of the British Society of Gastroenterology, and by unrestricted educational grants from AbbVie Inc, USA, Merck Sharp & Dohme Ltd, UK, NAPP Pharmaceuticals Ltd, UK, Pfizer Ltd, USA, Celltrion Healthcare, South Korea, and Cure Crohn's Colitis (Scottish IBD Charity). DNA methylation processing was supported through a sponsored research agreement with AbbVie Inc. The drug and anti-drug antibody assays were provided at reduced cost by Immundiagnostik AG. Laboratory tests were undertaken by the Exeter Blood Sciences Laboratory at the Royal Devon & Exeter National Health Service Trust (https://www.exeterlaboratory.com). The sponsor of the PANTS study is the Royal Devon and Exeter National Health Service Foundation Trust. None of the listed funders had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and decision to submit the manuscript for publication.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The sponsor of the study was the Royal Devon and Exeter NHS Foundation Trust. The South West Research Ethics committee approved the study (REC Reference: 12/SW/0323) in January 2013. The funders of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Individual participant de-identified data that underlie the results reported in this article will be available immediately after publication for a period of 5 years. The data will be made available to investigators whose proposed use of the data has been approved by an independent review committee. Analyses will be restricted to the aims in the approved proposal. Proposals should be directed to tariq.ahmad1@nhs.net. To gain access data requestors will need to sign a data access agreement. 

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