Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome.
Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome.
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DOI：
10.3389/fpain.2021.775386
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hall KT
中科院分区：
文献类型：
--
作者：
Wang RS;Lembo AJ;Kaptchuk TJ;Cheng V;Nee J;Iturrino J;Rao M;Loscalzo J;Silvester JA;Hall KT
背景和目的：肠易激综合征（IBS）是一种肠-脑相互作用的功能性疼痛障碍，在随机临床试验（rct）中，其特点是安慰剂反应高。儿茶酚- o -甲基转移酶（COMT） rs4680编码高活性（val）或低活性（met）酶变体，先前在IBS RCT中与安慰剂对假针灸的反应相关。在随机对照试验中，研究COMT效应并确定影响安慰剂反应的新基因组因素对于确定潜在机制以及预测和管理安慰剂至关重要。方法：IBS患者（N = 188）随机接受三种安慰剂相关干预，即双盲安慰剂（DBP）、开放标签安慰剂（OLP）或单纯试验入组，不进行安慰剂治疗[无安慰剂（即无药丸）治疗对照（NPC）]，为期6周。检查COMT rs4680、基因集和全基因组提示（p < 10−5）位点对所有参与者肠易激症状严重程度评分（IBS-SSS）的影响。结果：具有rs4680 met （met/met）的IBS纯合子的参与者在所有组中都有最大的改善，DBP (β (SE),−89.4(42.3)，与val/val相比有显著更大的改善；P = 0.04)。12个全基因组提示位点形成了一个与EGR1高度相关的基因调控网络，EGR1是一种转录因子，参与安慰剂相关的学习、记忆、应激和奖励反应过程。在所有治疗组的终点，外周血单核细胞（PBMC）中的EGR1基因表达均显著降低（对数倍变化，- 0.15;p = 0.02）。基因集富集分析返回了三个全基因组范围内重要的本体术语（GO:0032968， GO:0070934和GO:0070937）与转录调控相关，GO:0003918与DNA拓扑异构酶调控相关。结论：这些结果提示了对不同形式安慰剂反应的共同分子机制，可能为个性化IBS治疗和安慰剂反应预测提供信息。临床试验注册：ClinicalTrials.gov，标识符：NCT0280224。
Background and Aims: 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 (COMT) 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 COMT 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. Methods: Participants with IBS (N = 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. COMT rs4680, gene-set, and genome-wide suggestive (p < 10−5) loci effects on irritable bowel symptom severity score (IBS-SSS) across all participants were examined. Results: 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); p = 0.04). Twelve genome-wide suggestive loci formed a gene regulatory network highly connected to EGR1, a transcription factor involved in placebo-related processes of learning, memory, and response to stress and reward. EGR1 gene expression in peripheral blood mononuclear cells (PBMC) was significantly reduced at the endpoint across all treatment arms (log fold-change, −0.15; p = 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. Conclusion: These results suggest common molecular mechanisms in response to varying forms of placebo that may inform personalized IBS treatment and placebo response prediction. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT0280224.
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DOI：
10.1038/tpj.2016.53
发表时间：
2016-10
期刊：
The pharmacogenomics journal
影响因子：
--
作者：
Hall KT;Kossowsky J;Oberlander TF;Kaptchuk TJ;Saul JP;Wyller VB;Fagermoen E;Sulheim D;Gjerstad J;Winger A;Mukamal KJ
通讯作者：
Mukamal KJ
影响因子：
64.5
作者：
Ahuja, Rashmi;Pinyol, Roser;Qualmann, Britta
通讯作者：
Qualmann, Britta
影响因子：
9.8
作者：
Chey, William D.;Lembo, Anthony J.;Johnston, Jeffrey M.
通讯作者：
Johnston, Jeffrey M.
影响因子：
10.3
作者：
Hall, Kathryn T.;Buring, Julie E.;Chasman, Daniel, I
通讯作者：
Chasman, Daniel, I
影响因子：
2.1
作者：
Hall, Kathryn T.;Loscalzo, Joseph;Kaptchuk, Ted J.
通讯作者：
Kaptchuk, Ted J.