AUTHOR=Wang Rui-Sheng , Lembo Anthony J. , Kaptchuk Ted J. , Cheng Vivian , Nee Judy , Iturrino Johanna , Rao Meenakshi , Loscalzo Joseph , Silvester Jocelyn A. , Hall Kathryn T. 

TITLE=Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome

JOURNAL=Frontiers in Pain Research

VOLUME=2

YEAR=2022

URL=https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2021.775386

DOI=10.3389/fpain.2021.775386

ISSN=2673-561X

ABSTRACT=<p><bold>Background and Aims:</bold> Irritable bowel syndrome (IBS), a functional pain disorder of gut-brain interactions, is characterized by a high placebo response in randomized clinical trials (RCTs). Catechol-O-methyltransferase (<italic>COMT</italic>) rs4680, which encodes high-activity (val) or low-activity (met) enzyme variants, was previously associated with placebo response to sham-acupuncture in an IBS RCT. Examining <italic>COMT</italic> effects and identifying novel genomic factors that influence response to placebo pills is critical to identifying underlying mechanisms and predicting and managing placebos in RCTs.</p><p><bold>Methods:</bold> Participants with IBS (<italic>N</italic> = 188) were randomized to three placebo-related interventions, namely, double-blind placebo (DBP), open-label placebo (OLP), or simply trial enrollment without placebo treatment [no placebo (i.e., no pill) treatment control (NPC)], for 6 weeks. <italic>COMT</italic> rs4680, gene-set, and genome-wide suggestive (<italic>p</italic> &lt; 10<sup>−5</sup>) loci effects on irritable bowel symptom severity score (IBS-SSS) across all participants were examined.</p><p><bold>Results:</bold> Participants with IBS homozygous for rs4680 met (met/met) had the greatest improvement across all arms, with significantly greater improvement compared to val/val in DBP (beta (SE), −89.4 (42.3); <italic>p</italic> = 0.04). Twelve genome-wide suggestive loci formed a gene regulatory network highly connected to <italic>EGR1</italic>, a transcription factor involved in placebo-related processes of learning, memory, and response to stress and reward. <italic>EGR1</italic> gene expression in peripheral blood mononuclear cells (PBMC) was significantly reduced at the endpoint across all treatment arms (log fold-change, −0.15; <italic>p</italic> = 0.02). Gene-set enrichment analysis returned three genome-wide significant ontology terms (GO:0032968, GO:0070934, and GO:0070937) linked to transcription regulation and GO:0003918 associated with DNA topoisomerase regulation.</p><p><bold>Conclusion:</bold> These results suggest common molecular mechanisms in response to varying forms of placebo that may inform personalized IBS treatment and placebo response prediction.</p><p><bold>Clinical Trial Registration:</bold><ext-link ext-link-type="uri" xlink:href="https://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>, Identifier: NCT0280224.</p>