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

2022 ◽  
Vol 2 ◽  
Author(s):  
Rui-Sheng Wang ◽  
Anthony J. Lembo ◽  
Ted J. Kaptchuk ◽  
Vivian Cheng ◽  
Judy Nee ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
Mononuclear Cells ◽  
Placebo Response ◽  
Placebo Treatment ◽  
Gene Set Enrichment Analysis ◽  
Gene Set ◽  
Genome Wide ◽  
Irritable Bowel

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.

scholarly journals Gene set enrichment analysis for genome-wide DNA methylation data

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jovana Maksimovic ◽  
Alicia Oshlack ◽  
Belinda Phipson
Keyword(s):  
Dna Methylation ◽  
Enrichment Analysis ◽  
R Package ◽  
Gene Set Enrichment Analysis ◽  
Methylation Array ◽  
Gene Set ◽  
Genome Wide ◽  
Genome Methylation ◽  
Unbiased Gene ◽  
Gene Set Testing

AbstractDNA methylation is one of the most commonly studied epigenetic marks, due to its role in disease and development. Illumina methylation arrays have been extensively used to measure methylation across the human genome. Methylation array analysis has primarily focused on preprocessing, normalization, and identification of differentially methylated CpGs and regions. GOmeth and GOregion are new methods for performing unbiased gene set testing following differential methylation analysis. Benchmarking analyses demonstrate GOmeth outperforms other approaches, and GOregion is the first method for gene set testing of differentially methylated regions. Both methods are publicly available in the missMethyl Bioconductor R package.

scholarly journals Integrated Insight into the Molecular Mechanisms of Spontaneous Abortion during Early Pregnancy in Pigs

2021 ◽  
Vol 22 (12) ◽  
pp. 6644
Author(s):  
Xupeng Zang ◽  
Ting Gu ◽  
Wenjing Wang ◽  
Chen Zhou ◽  
Yue Ding ◽  
...  
Keyword(s):  
Immune Response ◽  
Spontaneous Abortion ◽  
Molecular Mechanisms ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Gene Set ◽  
Cerna Network ◽  
Major Interest ◽  
End Stage ◽  
Insight Into

Due to the high rate of spontaneous abortion (SAB) in porcine pregnancy, there is a major interest and concern on commercial pig farming worldwide. Whereas the perturbed immune response at the maternal–fetal interface is an important mechanism associated with the spontaneous embryo loss in the early stages of implantation in porcine, data on the specific regulatory mechanism of the SAB at the end stage of the implantation remains scant. Therefore, we used high-throughput sequencing and bioinformatics tools to analyze the healthy and arresting endometrium on day 28 of pregnancy. We identified 639 differentially expressed lncRNAs (DELs) and 2357 differentially expressed genes (DEGs) at the end stage of implantation, and qRT-PCR was used to verify the sequencing data. Gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immunohistochemistry analysis demonstrated weaker immune response activities in the arresting endometrium compared to the healthy one. Using the lasso regression analysis, we screened the DELs and constructed an immunological competitive endogenous RNA (ceRNA) network related to SAB, including 4 lncRNAs, 11 miRNAs, and 13 genes. In addition, Blast analysis showed the applicability of the constructed ceRNA network in different species, and subsequently determined HOXA-AS2 in pigs. Our study, for the first time, demonstrated that the SAB events at the end stages of implantation is associated with the regulation of immunobiological processes, and a specific molecular regulatory network was obtained. These novel findings may provide new insight into the possibility of increasing the litter size of sows, making pig breeding better and thus improving the efficiency of animal husbandry production.

scholarly journals Pharmacology of Antispasmodic Drugs Used in Management of Irritable Bowel Syndrome

Doctor Ru ◽  
2021 ◽  
Vol 20 (4) ◽  
pp. 46-54
Author(s):  
Е.N. Kareva ◽  
◽  
◽  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Russian Federation ◽  
Molecular Mechanisms ◽  
Cell Voltage ◽  
Neural Systems ◽  
Pharmacokinetic Parameters ◽  
Bowel Disorders ◽  
Intestinal Motility Disorders ◽  
The Russian Federation ◽  
Irritable Bowel

Objective of the Review: To describe and compare some pharmacodynamic and pharmacokinetic parameters of antispasmodic drugs used in complex management of irritable bowel syndrome (IBS) in the Russian Federation. Key Points. IBS is a chronic recurrent disease associated with abdominal pain and bowel disorders. The key factors of IBS pathogenesis include intestinal motility disorders and visceral hypersensitivity. Both processes are controlled by endocrine and neural systems. In a target cell, voltage-operated calcium channels mediate neuronal signals for unstriped muscles to contract and for glands to start secreting. Antispasmodic drugs are a group of products that have been used for IBS management for decades. The review describes contemporary idea of molecular mechanisms to control contraction of GIT muscle cells and a comparison of antispasmodic drugs used in complex therapy of IBS in the Russian Federation. Their key pharmacodynamic and pharmacokinetic characteristics are discussed. Conclusion. The fundamental difference of mebeverine (Duspatalin) is its ability to normalise bowel motility in patients with IBS without the need in complete motility suppression. Also, its inability to block muscarinic receptors and stimulate opioid receptors is another advantage in improving the quality of life of patients. Keywords: pharmacodynamics, pharmacokinetics, antispasmodic drugs, therapy of irritable bowel syndrome, mebeverine.

scholarly journals Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Emrin Horgusluoglu-Moloch ◽  
◽  
Shannon L. Risacher ◽  
Paul K. Crane ◽  
Derrek Hibar ◽  
...  
Keyword(s):  
Association Analysis ◽  
Adult Neurogenesis ◽  
Enrichment Analysis ◽  
Hippocampal Volume ◽  
Imaging Genetics ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Genome Wide

Abstract Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer’s Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.

Placebo Response in Clinical Randomized Trials of Analgesics in Migraine

Cephalalgia ◽  
2003 ◽  
Vol 23 (7) ◽  
pp. 487-490 ◽  
Author(s):  
L Bendtsen ◽  
P Mattsson ◽  
J-A Zwart ◽  
RB Lipton
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Response Rate ◽  
International Headache Society ◽  
Placebo Response ◽  
Patient Characteristics ◽  
Placebo Treatment ◽  
Primary Efficacy ◽  
Efficacy Parameter ◽  
Efficacy Measure

The objective was to assess the placebo response in randomized clinical trials of analgesics in the treatment of migraine attacks. We included placebo-controlled studies that used the criteria of the International Headache Society for the diagnosis of migraine and headache response as the primary efficacy parameter. In the 11 studies that qualified for inclusion, headache response occurred after placebo treatment in 7-50% of the migraineurs with an average placebo response rate of 30% (95% confidence interval (CI) 23-36). Two hours after treatment with placebo an average of 9% (95% CI 7-12, range 7-17%) of the patients were found to be pain free. In conclusion, the average headache response rate to placebo was 30% in randomized clinical trials of analgesics in migraine with a tremendous variation among studies. Placebo response rates vary with the choice of primary efficacy measure as well as patient characteristics and study design.

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