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Javelle F, Dao G, Ringleb M, Pulverer W, Bloch W. Exploring the association between serotonin transporter promoter region methylation levels and depressive symptoms: a systematic review and multi-level meta-analysis. Transl Psychiatry 2025; 15:161. [PMID: 40319044 PMCID: PMC12049537 DOI: 10.1038/s41398-025-03356-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 03/17/2025] [Accepted: 03/27/2025] [Indexed: 05/07/2025] Open
Abstract
Depressive disorders result from complex interactions among genetic, epigenetic, and environmental factors. DNA methylation, a key epigenetic mechanism, is crucial in understanding depressive symptoms development. The serotonin transporter gene (5-HTT) and its polymorphisms, like 5-HTTLPR, have been extensively studied in relation to depression, yet conflicting findings regarding the association between 5-HTT promoter methylation and depressive symptoms persist, largely due to methodological differences. Thus, this systematic review and meta-analysis aims to assess (1) 5-HTT promoter methylation levels between depressed and non-depressed conditions and (2) the association between 5-HTT methylation and depressive symptoms severity. We searched PubMed, Google Scholar, and Web of Science from inception to January 15th, 2025 (PROSPERO: CRD42023355414) and performed two independent multi-level meta-analyses to answer our aims. Twenty-four trials were included in the systematic review. All reported effects carried potential for bias. The meta-analysis for depression occurrence (12 studies - 2028 subjects - 127 effects) indicated no significant effect (Hedges'g = 0.06) with moderate within- and low between-study heterogeneity. The depression severity analysis (14 studies - 2296 subjects - 116 effects) revealed a null effect size (Fisher's Z = 0.05), with no within- and moderate between-study heterogeneity. Asymmetry was detected for both meta-analyses. Moderator analyses demonstrated no significant effects of depression severity, methylation techniques, single-CpG sites, cell types assessed, age, and female percentage. This comprehensive review provides insights into the intricate interplay between 5-HTT promoter methylation and depressive symptoms. Furthermore, it offers well-considered recommendations for future research endeavors and delineates guidelines for reporting methylation research.
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Affiliation(s)
- F Javelle
- NeuroPsychoImmunology research unit, Department for Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Cologne, Germany.
| | - G Dao
- NeuroPsychoImmunology research unit, Department for Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Cologne, Germany
- University of Cologne, Cologne, Germany
| | - M Ringleb
- NeuroPsychoImmunology research unit, Department for Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Cologne, Germany
- Department of Movement Science, University of Münster, Münster, Germany
- Department of Sports Medicine and Health Promotion, Friedrich-Schiller-University Jena, Jena, Germany
| | - W Pulverer
- Austrian Institute of Technology, Vienna, Austria
| | - W Bloch
- Department for Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Cologne, Germany
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Trush EA, Karchevskaya AE, Maslennikov RV, Poluektova EA, Shifrin OS, Ivashkin VT. Single Nucleotide Polymorphisms, Associated with Increased Risk of Irritable Bowel Syndrome with Predominant Constipation: A Meta Analysis. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:62-77. [DOI: 10.22416/1382-4376-2024-34-3-62-77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Introduction. Genetic predisposition in combination with environmental factors and the patient’s psychological and emotional state play a key role in the development of irritable bowel syndrome (IBS). Studies of association between genetic polymorphisms and IBS can help in understanding the key pathophysiological mechanisms. To date, 11 meta-analyses on this issue have been published, however, none of them comprehensively summarize the data on the prevalence of genetic polymorphisms in IBS with predominant constipation (IBS-C).Aim: to summarize the published data on the impact of genetic polymorphisms on the risk of IBS-C.Materials and methods. A literature search was performed in the PubMed and Scopus databases. Identified studies were used for a meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Publications investigating genetic polymorphisms in patients with IBS-C were included in this analysis.Results. A total of 34 studies met the inclusion criteria. The collected data were sufficient to conduct a meta-analysis on polymorphisms of three of the listed genes: SLC6A4 (10 articles), GNB3 (5 articles), ADRA2A (4 articles). No significant association was found between the SLC6A4 (5-HTTLPR) polymorphism, GNB3 c.825C > T (rs5443) polymorphism and either IBS or IBS-C. It was found that ADRA2A 1291C>G polymorphism was significantly associated with both IBS and IBS-C.Conclusions. Our meta-analysis revealed that ADRA2A 1291C>G polymorphism was significantly associated with both IBS and IBS-C in the mixed population. Neither homozygous nor heterozygous variants of the SLC6A4 (5-HTTLPR) polymorphism and GNB3 C825T polymorphism were associated with either IBS-C or IBS as a whole.
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Affiliation(s)
- E. A. Trush
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - A. E. Karchevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - R. V. Maslennikov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - E. A. Poluektova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. S. Shifrin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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Camilleri M, Zhernakova A, Bozzarelli I, D'Amato M. Genetics of irritable bowel syndrome: shifting gear via biobank-scale studies. Nat Rev Gastroenterol Hepatol 2022; 19:689-702. [PMID: 35948782 DOI: 10.1038/s41575-022-00662-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 12/19/2022]
Abstract
The pathophysiology of irritable bowel syndrome (IBS) is multifactorial and probably involves genetic predisposition and the effect of environmental factors. Unlike other gastrointestinal diseases with a heritable component, genetic research in IBS has been scarce and mostly characterized by small underpowered studies, leading to inconclusive results. The availability of genomic and health-related data from large international cohorts and population-based biobanks offers unprecedented opportunities for long-awaited, well-powered genetic studies in IBS. This Review focuses on the latest advances that provide compelling evidence for the importance of genes involved in the digestion of carbohydrates, ion channel function, neurotransmitters and their receptors, neuronal pathways and the control of gut motility. These discoveries have generated novel information that might be further refined for the identification of predisposed individuals and selection of management strategies for patients. This Review presents a conceptual framework, the advantages and potential limitations of modern genetic research in IBS, and a summary of available evidence.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | | | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain. .,Ikerbasque, Basque Foundation for Science, Bilbao, Spain. .,Department of Medicine and Surgery, LUM University, Casamassima, Italy.
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Unraveling the Contribution of Serotonergic Polymorphisms, Prefrontal Alpha Asymmetry, and Individual Alpha Peak Frequency to the Emotion-Related Impulsivity Endophenotype. Mol Neurobiol 2022; 59:6062-6075. [PMID: 35854179 PMCID: PMC9463349 DOI: 10.1007/s12035-022-02957-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 07/04/2022] [Indexed: 12/03/2022]
Abstract
The unique contribution of the serotonin transporter-linked polymorphic region (5-HTTLPR), intronic region 2 (STin2), and monoamine oxidase A (MAO-A) genes to individual differences in personality traits has been widely explored, and research has shown that certain forms of these polymorphisms relate to impulsivity and impulsivity-related disorders. Humans showing these traits are also described as having an asymmetrical prefrontal cortical activity when compared to others. In this explorative study, we examine the relationship between serotonergic neurotransmission polymorphisms, cortical activity features (prefrontal alpha asymmetry, individual alpha peak frequency [iAPF]), emotion-related and non-emotion-related impulsivity in humans. 5-HTTLPR, MAO-A, and STin2 polymorphisms were assessed in blood taken from 91 participants with high emotion-related impulsivity levels. Sixty-seven participants completed resting electroencephalography and a more comprehensive impulsivity index. In univariate analyses, iAPF correlated with both forms of emotion-related impulsivity. In multiple linear regression models, 5-HTTLPR polymorphism (model 1, adj. R2 = 15.2%) and iAPF were significant interacting predictors of emotion-related impulsivity, explaining a large share of the results’ variance (model 2, adj. R2 = 21.2%). Carriers of the low transcriptional activity 5-HTTPLR and MAO-A phenotypes obtained higher emotion-related impulsivity scores than others did. No significant results were detected for non-emotion-related impulsivity or for a form of emotion-related impulsivity involving cognitive/motivational reactivity to emotion. Our findings support an endophenotypic approach to impulsivity, showing that tri-allelic 5-HTTLPR polymorphism, iAPF, and their interaction are relevant predictors of one form of emotion-related impulsivity.
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The Associations of Single Nucleotide Polymorphisms with Risk and Symptoms of Irritable Bowel Syndrome. J Pers Med 2022; 12:jpm12020142. [PMID: 35207633 PMCID: PMC8878682 DOI: 10.3390/jpm12020142] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/10/2022] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
Although several risk single nucleotide polymorphisms (SNPs) have been found to play an important role in etiology of irritable bowel syndrome (IBS), the findings are inconsistent. A descriptive correlational design was used to analyze the baseline data of a randomized controlled trial including participants with IBS and healthy controls (HC). Pain severity and interference, anxiety, sleep, and fatigue were measured using the Brief Pain Inventory (BPI) and patient-reported outcomes measurement information system (PROMIS). Fisher’s exact test and multivariate linear regression were used to investigate the associations between IBS risk alleles and IBS symptoms. Participants were predominantly female, white, and had an average age of 21.13 ± 2.42 years. Polymorphisms within TNFSF15 (rs4263839), SLC6A4 5-HTTLPR, HTR3A (rs1062613), and OXTR (rs2254298) were associated with IBS risk, and TNFSF15 (rs4263839), COMT (rs6269), SLC6A4 5-HTTLPR polymorphisms were associated with pain severity. TNFSF15 (rs4263839) and COMT (rs4680; rs4633) genotypes were associated with sleep disturbance, and the ADRA1D SNP rs1556832 was associated with fatigue in both IBS and HC groups. Genotypic differences were associated with IBS risk and symptoms including abdominal pain, sleep disturbance, and fatigue. Further investigation is warranted to reveal the mechanisms by which these genetic variations influence the dynamic nature of IBS symptoms over time.
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Holland AM, Bon-Frauches AC, Keszthelyi D, Melotte V, Boesmans W. The enteric nervous system in gastrointestinal disease etiology. Cell Mol Life Sci 2021; 78:4713-4733. [PMID: 33770200 PMCID: PMC8195951 DOI: 10.1007/s00018-021-03812-y] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/20/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut-brain interaction, inflammatory bowel diseases, and colorectal cancer.
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Affiliation(s)
- Amy Marie Holland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ana Carina Bon-Frauches
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Daniel Keszthelyi
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM-School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Veerle Melotte
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Werend Boesmans
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
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Gunn D, Garsed K, Lam C, Singh G, Lingaya M, Wahl V, Niesler B, Henry A, Hall IP, Whorwell P, Spiller R. Abnormalities of mucosal serotonin metabolism and 5-HT 3 receptor subunit 3C polymorphism in irritable bowel syndrome with diarrhoea predict responsiveness to ondansetron. Aliment Pharmacol Ther 2019; 50:538-546. [PMID: 31342534 PMCID: PMC6772086 DOI: 10.1111/apt.15420] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/10/2019] [Accepted: 06/25/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Irritable bowel syndrome with diarrhoea (IBS-D) is a common condition, greatly reducing the quality of life with few effective treatment options available. AIM To report the beneficial response shown in our trial with the 5-hydroyxtryptamine (5-HT) receptor 3 antagonist, ondansetron in IBS-D METHODS: A randomised, placebo-controlled, cross-over trial of 5 weeks of ondansetron versus placebo in 125 patients meeting modified Rome III criteria for IBS-D as previously described. Patients were compared to 21 healthy controls. 5-HT and 5-HIAA were measured in rectal biopsies. Whole gut transit time was assessed using a radio-opaque marker technique. Whole blood DNA was genotyped for an insertion polymorphism in the promoter region of the serotonin transporter gene SLC6A4, as well as single nucleotide polymorphisms (SNPs) of the tryptophan hydroxylase gene TPH1 and 5-HT3 receptor genes HTR3A, C and E. RESULTS Patients' biopsies showed significantly higher 5-HIAA levels (2.1 (1.2-4.2) pmol/mg protein vs 1.1 (0.4-1.5) in controls, P < .0001). 39 patients used < 4 mg/d ("super-responders") while 55 required ≥ 4 mg/d. 5-HT concentrations in rectal biopsies were significantly lower in super-responders (21.3 (17.0-31.8) vs 37.7 (21.4-61.4), P = .0357) and the increase in transit time on ondansetron was significantly greater (15.6 (1.8-31) hours vs 3.9 (-5.1-17.9) hours). Stool consistency responders were more likely to carry the CC genotype of the SNP p.N163K rs6766410 of the HTR3C gene (33% vs 14%, P = .0066). CONCLUSION IBS-D patients have significant abnormalities in mucosal 5-HT metabolism. Those with the lowest concentration of 5-HT in rectal biopsies showed the greatest responsiveness to ondansetron.
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Affiliation(s)
- David Gunn
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK,Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
| | | | - Ching Lam
- Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation TrustSheffieldUK
| | - Gulzar Singh
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK,Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
| | - Melanie Lingaya
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK,Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
| | - Verena Wahl
- Department of Human Molecular Genetics, Institute of Human GeneticsUniversity Hospital Heidelberg and Interdisciplinary Center for Neurosciences (IZN), University of HeidelbergHeidelbergGermany
| | - Beate Niesler
- Department of Human Molecular Genetics, Institute of Human GeneticsUniversity Hospital Heidelberg and Interdisciplinary Center for Neurosciences (IZN), University of HeidelbergHeidelbergGermany
| | - Amanda Henry
- Department of Therapeutics and Molecular MedicineNIHR Nottingham Biomedical Research CentreNottinghamUK
| | - Ian P. Hall
- Department of Therapeutics and Molecular MedicineNIHR Nottingham Biomedical Research CentreNottinghamUK
| | - Peter Whorwell
- Department of NeurogastroenterologyUniversity of South Manchester Wythenshawe General HospitalManchesterUK
| | - Robin Spiller
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK,Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
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Hellström PM. Pathophysiology of the irritable bowel syndrome - Reflections of today. Best Pract Res Clin Gastroenterol 2019; 40-41:101620. [PMID: 31594651 DOI: 10.1016/j.bpg.2019.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 01/31/2023]
Abstract
Irritable bowel syndrome (IBS) is a chronic gastrointestinal symptom complex defined by abdominal pain and disturbed bowel habits over 3 months within a period of 6 months, in absence of any identifiable organic pathology. Over the years, speculations of the pathophysiology of IBS has moved from elusive central nervous symptoms impinging on psychosomatic disease, to objective signs of intestinal fermentation with abdominal bloating and intestinal dysmotility. The specific subgroup of post-infectious IBS is of special interest since it opens the possibility of dysbiosis as the pivotal point for development of IBS in association with traveler's diarrhea or antibiotic treatment with ensuing dysbiosis and abdominal symptoms that may resolve over decades. The undefined disease mechanisms that take place within the gut seem responsible for the gut-brain signaling leading to activation of brain centers that drive the clinical picture of IBS, further modulated by the patient's social background and previous lifetime events.
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Affiliation(s)
- Per M Hellström
- Department of Medical Sciences, Gastroenterology Unit, Uppsala University, Bldg 40, 5th Floor, SE-75185, Uppsala, Sweden.
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Hudon Thibeault AA, Sanderson JT, Vaillancourt C. Serotonin-estrogen interactions: What can we learn from pregnancy? Biochimie 2019; 161:88-108. [PMID: 30946949 DOI: 10.1016/j.biochi.2019.03.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/28/2019] [Indexed: 02/07/2023]
Abstract
We have reviewed the scientific literature related to four diseases in which to serotonin (5-HT) is involved in the etiology, herein named 5-HT-linked diseases, and whose prevalence is influenced by estrogenic status: depression, migraine, irritable bowel syndrome and eating disorders. These diseases all have in common a sex-dimorphic prevalence, with women more frequently affected than men. The co-occurrence between these 5-HT-linked diseases suggests that they have common physiopathological mechanisms. In most 5-HT-linked diseases (except for anorexia nervosa and irritable bowel syndrome), a decrease in the serotonergic tone is observed and estrogens are thought to contribute to the improvement of symptoms by stimulating the serotonergic system. Human pregnancy is characterized by a unique 5-HT and estrogen synthesis by the placenta. Pregnancy-specific disorders, such as hyperemesis gravidarum, gestational diabetes mellitus and pre-eclampsia, are associated with a hyperserotonergic state and decreased estrogen levels. Fetal programming of 5-HT-linked diseases is a complex phenomenon that involves notably fetal-sex differences, which suggest the implication of sex steroids. From a mechanistic point of view, we hypothesize that estrogens regulate the serotonergic system, resulting in a protective effect against 5-HT-linked diseases, but that, in turn, 5-HT affects estrogen synthesis in an attempt to retrieve homeostasis. These two processes (5-HT and estrogen biosynthesis) are crucial for successful pregnancy outcomes, and thus, a disruption of this 5-HT-estrogen relationship may explain pregnancy-specific pathologies or pregnancy complications associated with 5-HT-linked diseases.
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Affiliation(s)
- Andrée-Anne Hudon Thibeault
- INRS-Institut Armand-Frappier, 531, boulevard des Prairies, Laval, QC, H7V 1B7, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (Cinbiose), Université du Québec à Montréal, C.P.8888, succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
| | - J Thomas Sanderson
- INRS-Institut Armand-Frappier, 531, boulevard des Prairies, Laval, QC, H7V 1B7, Canada.
| | - Cathy Vaillancourt
- INRS-Institut Armand-Frappier, 531, boulevard des Prairies, Laval, QC, H7V 1B7, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (Cinbiose), Université du Québec à Montréal, C.P.8888, succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
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Grzesiak M, Beszłej JA, Waszczuk E, Szechiński M, Szewczuk-Bogusławska M, Frydecka D, Dobosz T, Jonkisz A, Lebioda A, Małodobra M, Mulak A. Serotonin-Related Gene Variants in Patients with Irritable Bowel Syndrome and Depressive or Anxiety Disorders. Gastroenterol Res Pract 2017; 2017:4290430. [PMID: 28951738 PMCID: PMC5603736 DOI: 10.1155/2017/4290430] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 05/29/2017] [Accepted: 07/05/2017] [Indexed: 12/20/2022] Open
Abstract
AIM To assess the association of six polymorphisms in serotonin-related genes with depressive or anxiety disorders in patients with irritable bowel syndrome (IBS). METHODS The lifetime prevalence of depressive and anxiety disorders was assessed in 95 IBS patients (85% women) using the Munich version of the Composite International Diagnostic Interview (CIDI). IBS was diagnosed according to the Rome III criteria. SCL6A4 HTTLPR polymorphism (rs4795541) was determined using PCR-based method. Single-nucleotide polymorphisms in HTR1A (rs6295), HTR2A (rs6313 and rs6311), HTR2C (rs6318), and TPH1 (rs1800532) were detected by minisequencing method. RESULTS IBS patients with depressive disorders were characterized by higher frequency of 5-HTTLPR L allele in comparison to IBS patients with anxiety disorders. The lower frequency of 1438 A allele in HTR2A was found in IBS patients with depressive disorders in comparison to IBS patients without mental disorders. The lower G allele frequency in HTR2C rs6318 polymorphism among IBS patients with anxiety disorders was also observed. CONCLUSIONS Our results provide further evidence for the involvement of SLC6A4 rs4795541 and HTR2A rs6311 polymorphisms in the pathophysiology of depressive disorders in IBS patients. The new findings indicate that HTR2C rs6318 polymorphism may be associated with the susceptibility to anxiety disorders in IBS patients.
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Affiliation(s)
| | | | - Ewa Waszczuk
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Wroclaw, Poland
| | - Marcin Szechiński
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
| | | | - Dorota Frydecka
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
| | - Tadeusz Dobosz
- Molecular Techniques Unit, Department of Forensic Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Anna Jonkisz
- Molecular Techniques Unit, Department of Forensic Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Arleta Lebioda
- Molecular Techniques Unit, Department of Forensic Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Małgorzata Małodobra
- Molecular Techniques Unit, Department of Forensic Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Agata Mulak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Wroclaw, Poland
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Mohammadi M, Tahmasebi Abdar H, Mollaei HR, Hajghani H, Baneshi MR, Hayatbakhsh MM. Serotonin Transporter Gene (SLC6A4) Polymorphism and Mucosal Serotonin Levels in Southeastern Iranian Patients with Irritable Bowel Syndrome. Middle East J Dig Dis 2017; 9:26-32. [PMID: 28316763 PMCID: PMC5308131 DOI: 10.15171/mejdd.2016.48] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND
Irritable bowel syndrome (IBS) is a digestive system disorder with an unknown etiology. Serotonin has a key role in the secretion and motility of the intestine. Polymorphism in serotonin re-uptake transporter (SERT or SLC6A4) gene may have a functional role in the gut of patients with IBS. The aims of the present study were to investigate the association between SLC6A4 gene polymorphism and IBS and to detect the correlation between rectal serotonin levels and IBS sub-types.
METHODS
SLC6A4 gene polymorphism in 131 patients with IBS and 211 healthy controls were analysed using the quantitative polymerase chain reaction high-resolution melting (qPCR-HRM) curve technique. Serotonin was measured in rectal biopsies of patients with IBS using the enzyme-linked immunosorbent assay (ELISA) method.
RESULTS
The patients were categorized into three groups: IBS with diarrhoea (IBS-D): 70 patients, IBS with constipation (IBS-C): 18 patients, and IBS with mixed symptoms (IBS-M): 43 patients. The frequency of SLC6A4 s/s and l/s genotypes was significantly higher in IBS-C than IBS-D, IBS-M, and controls (p=0.036). Serotonin levels were similar in IBS sub-types.
CONCLUSION
SLC6A4 polymorphism is a possible candidate gene associated with the pathogenesis of IBS-C. Although serotonin levels did not differ in rectal biopsies of IBS sub-types, further investigation is recommended.
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Affiliation(s)
- Mojgan Mohammadi
- Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran ; Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Tahmasebi Abdar
- Department of Gastroenterology, Afzalipour Hospital, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamid Reza Mollaei
- Department of Microbiology and Virology, Kerman University of Medical Sciences, Kerman, Iran
| | - Hossein Hajghani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Reza Baneshi
- Modeling in Health Research Centre, Institute of Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Mahdi Hayatbakhsh
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
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12
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Zhao JM, Chen L, Zhou CL, Shi Y, Li YW, Shang HX, Wu LY, Bao CH, Dou CZ, Wu HG. Comparison of Electroacupuncture and Moxibustion for Relieving Visceral Hypersensitivity in Rats with Constipation-Predominant Irritable Bowel Syndrome. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:9410505. [PMID: 27738447 PMCID: PMC5055954 DOI: 10.1155/2016/9410505] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 08/11/2016] [Indexed: 02/08/2023]
Abstract
Aim. To compare whether there is different effect between electroacupuncture (EA) and moxibustion (Mox) on visceral hypersensitivity (their analgesic effects) in constipation-predominant irritable bowel syndrome (C-IBS). Methods. EA at 1 mA and 3 mA and Mox at 43°C and 46°C were applied to the Shangjuxu (ST37, bilateral) acupoint in rats with C-IBS and normal rats. An abdominal withdrawal reflex (AWR) score was used to assess visceral hypersensitivity. Toluidine blue staining was used to assess mast cell (MC) activity in colon of rats. Immunochemistry was used to measure 5-HT and 5-HT4 receptor expression in the colon. Results. AWR scores in all EA (1 mA and 3 mA) and Mox (43°C and 46°C) treatment groups after colorectal distention (CRD) stimulation pressure of 20, 40, 60, and 80 mmHg were significantly lower than those of the model (MC) group (P all < 0.01). The MC counts and degranulation rates in the colon of all EA and Mox treatment groups and the MC group were significantly higher than those of the NC group (P all < 0.01). MC degranulation rates in the colon of all EA and Mox treatment groups were lower than those of the MC group (P all < 0.05). 5-HT expression in colon of all EA and Mox treatment groups was significantly lower than that of the MC group (P all < 0.01), and 5-HT4R expression in colon of both EA groups was significantly higher than that of the MC group (P both < 0.01). Conclusion. EA and Mox treatments may both ameliorate visceral hypersensitivity at different degree in rats with C-IBS, and EA treatment was better than Mox.
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Affiliation(s)
- Ji-Meng Zhao
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Liu Chen
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ci-Li Zhou
- Shanghai Institute of Acupuncture-Moxibustion and Meridian, Shanghai 200030, China
| | - Yin Shi
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Shanghai Institute of Acupuncture-Moxibustion and Meridian, Shanghai 200030, China
| | - Yu-Wei Li
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hai-Xia Shang
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lu-Yi Wu
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Chun-Hui Bao
- Shanghai Institute of Acupuncture-Moxibustion and Meridian, Shanghai 200030, China
| | - Chuan-Zi Dou
- Shanghai Institute of Acupuncture-Moxibustion and Meridian, Shanghai 200030, China
| | - Huan-Gan Wu
- Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Shanghai Institute of Acupuncture-Moxibustion and Meridian, Shanghai 200030, China
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13
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Pigrau M, Rodiño-Janeiro BK, Casado-Bedmar M, Lobo B, Vicario M, Santos J, Alonso-Cotoner C. The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome. Neurogastroenterol Motil 2016; 28:463-86. [PMID: 26556786 DOI: 10.1111/nmo.12717] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/05/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intestinal homeostasis is a dynamic process that takes place at the interface between the lumen and the mucosa of the gastrointestinal tract, where a constant scrutiny for antigens and toxins derived from food and microorganisms is carried out by the vast gut-associated immune system. Intestinal homeostasis is preserved by the ability of the mucus layer and the mucosal barrier to keep the passage of small-sized and antigenic molecules across the epithelium highly selective. When combined and preserved, immune surveillance and barrier's selective permeability, the host capacity of preventing the development of intestinal inflammation is optimized, and viceversa. In addition, the brain-gut-microbiome axis, a multidirectional communication system that integrates distant and local regulatory networks through neural, immunological, metabolic, and hormonal signaling pathways, also regulates intestinal function. Dysfunction of the brain-gut-microbiome axis may induce the loss of gut mucosal homeostasis, leading to uncontrolled permeation of toxins and immunogenic particles, increasing the risk of appearance of intestinal inflammation, mucosal damage, and gut disorders. Irritable bowel syndrome is prevalent stress-sensitive gastrointestinal disorder that shows a female predominance. Interestingly, the role of stress, sex and gonadal hormones in the regulation of intestinal mucosal and the brain-gut-microbiome axis functioning is being increasingly recognized. PURPOSE We aim to critically review the evidence linking sex, and stress to intestinal barrier and brain-gut-microbiome axis dysfunction and the implications for irritable bowel syndrome.
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Affiliation(s)
- M Pigrau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B K Rodiño-Janeiro
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Casado-Bedmar
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B Lobo
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Vicario
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - J Santos
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - C Alonso-Cotoner
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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14
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Sasaki A, Sato N, Suzuki N, Kano M, Tanaka Y, Kanazawa M, Aoki M, Fukudo S. Associations between Single-Nucleotide Polymorphisms in Corticotropin-Releasing Hormone-Related Genes and Irritable Bowel Syndrome. PLoS One 2016; 11:e0149322. [PMID: 26882083 PMCID: PMC4755592 DOI: 10.1371/journal.pone.0149322] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 01/29/2016] [Indexed: 12/31/2022] Open
Abstract
UNLABELLED Irritable bowel syndrome (IBS) is a common functional disorder with distinct features of stress-related pathophysiology. A key mediator of the stress response is corticotropin-releasing hormone (CRH). Although some candidate genes have been identified in stress-related disorders, few studies have examined CRH-related gene polymorphisms. Therefore, we tested our hypothesis that single-nucleotide polymorphisms (SNPs) in CRH-related genes influence the features of IBS. METHODS In total, 253 individuals (123 men and 130 women) participated in this study. They comprised 111 IBS individuals and 142 healthy controls. The SNP genotypes in CRH (rs28364015 and rs6472258) and CRH-binding protein (CRH-BP) (rs10474485) were determined by direct sequencing and real-time polymerase chain reaction. The emotional states of the subjects were evaluated using the State-Trait Anxiety Inventory, Perceived Stress Scale, and the Self-rating Depression Scale. RESULTS Direct sequencing of the rs28364015 SNP of CRH revealed no genetic variation among the study subjects. There was no difference in the genotype distributions and allele frequencies of rs6472258 and rs10474485 between IBS individuals and controls. However, IBS subjects with diarrhea symptoms without the rs10474485 A allele showed a significantly higher emotional state score than carriers. CONCLUSIONS These results suggest that the CRH and CRH-BP genes have no direct effect on IBS status. However, the CRH-BP SNP rs10474485 has some effect on IBS-related emotional abnormalities and resistance to psychosocial stress.
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Affiliation(s)
- Ayaka Sasaki
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoko Sato
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoki Suzuki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiko Kano
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
- Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan
| | - Yukari Tanaka
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Motoyori Kanazawa
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masashi Aoki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shin Fukudo
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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15
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Gazouli M, Wouters MM, Kapur-Pojskić L, Bengtson MB, Friedman E, Nikčević G, Demetriou CA, Mulak A, Santos J, Niesler B. Lessons learned--resolving the enigma of genetic factors in IBS. Nat Rev Gastroenterol Hepatol 2016; 13:77-87. [PMID: 26726033 DOI: 10.1038/nrgastro.2015.206] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case-control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi)genetic research and provides a vision on how to address and improve (epi)genetic approaches in this complex disorder in the future.
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Affiliation(s)
- Maria Gazouli
- Department of Basic Sciences, Laboratory of Biology, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece
| | - Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Herestraat 49, Leuven 3000, Belgium
| | - Lejla Kapur-Pojskić
- Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Kemalbegova 10, 71.000 Sarajevo, Bosnia and Herzegovina
| | - May-Bente Bengtson
- Vestfold Hospital Trust, Tønsberg, Department of Internal Medicine, Division of Gastroenterology, P.O. Box 2168, 3103 Tønsberg, Norway
| | - Eitan Friedman
- The Suzanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Centre, 52621 Tel-Hashomer, Israel
| | - Gordana Nikčević
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 23 11010 Belgrade, Serbia
| | - Christiana A Demetriou
- Department of Electron Microscopy / Molecular Pathology, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus
| | - Agata Mulak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
| | - Javier Santos
- Neuro-immuno-gastroenterology Lab, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca. Department of Gastroenterology, Hospital Universitari Vall d'Hebron &Facultat de Medicina, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
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16
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Martinucci I, Blandizzi C, de Bortoli N, Bellini M, Antonioli L, Tuccori M, Fornai M, Marchi S, Colucci R. Genetics and pharmacogenetics of aminergic transmitter pathways in functional gastrointestinal disorders. Pharmacogenomics 2016; 16:523-39. [PMID: 25916523 DOI: 10.2217/pgs.15.12] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Functional gastrointestinal disorders (FGIDs) are highly prevalent syndromes, without evident underlying organic causes. Their pathogenesis is multifactorial in nature, with a combination of environmental and genetic factors contributing to their clinical manifestations, for which most of current treatments are not satisfactory. It is acknowledged that amine mediators (noradrenaline, dopamine and serotonin) play pivotal regulatory actions on gut functions and visceral sensation. In addition, drugs of therapeutic interest for FGIDs act on these transmitter pathways. The present article reviews current knowledge on the impact of genetics and pharmacogenetics of aminergic pathways on FGID pathophysiology, clinical presentations, symptom severity and medical management, in an attempt of highlighting the most relevant evidence and point out issues that should be addressed in future investigations.
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Affiliation(s)
- Irene Martinucci
- Gastroenterology Unit, Department of Translational Research & New Technologies in Medicine, University of Pisa, Via Paradisa 2, I-56124 Pisa, Italy
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17
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Gressier F, Calati R, Serretti A. 5-HTTLPR and gender differences in affective disorders: A systematic review. J Affect Disord 2016; 190:193-207. [PMID: 26519640 DOI: 10.1016/j.jad.2015.09.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 09/12/2015] [Accepted: 09/15/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Serotonin transporter-linked polymorphic region (5-HTTLPR) variants have been extensively studied in psychiatric disorders. Although gender effects have been reported, they have not been comprehensively reviewed. The aim of our study was to summarize literature findings on 5-HTTLPR and gender differences in affective disorders. METHODS A systematic search of PubMed, ISI Web of Knowledge, and PsycINFO databases was performed for dates until January 2015. The included articles (n=78) analyzed the association between 5-HTTLPR and affective spectrum disorders, taking into account gender. The quality of each study was assessed through STROBE and CONSORT. RESULTS 5-HTTLPR modulation of affective disorders varied by gender. The S allele (or SS genotype) seemed to be differently associated with an increased risk of depression, depressive symptoms, anxiety traits and symptoms, and symptoms of internalizing behavior among women and an increased risk of aggressiveness, conduct disorder and symptom counts of externalizing behavior among men. Moreover, the presence of stressful life events reinforced the association. Interestingly, these differences seemed to begin with adolescence and were not consistent among the elderly, suggesting a plausible role of hormonal fluctuations. LIMITATIONS The review is limited by the small number of included papers, due to the paucity of information in the literature regarding 5-HTTLPR and gender. CONCLUSIONS 5-HTTLPR variants may exert a differential modulation on a number of features depending on gender. Further studies are needed to more deeply investigate the effect of 5-HTTLPR×gender on the modulation of affective disorders.
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Affiliation(s)
- F Gressier
- INSERM UMR 1178, Univ Paris Sud, Department of Psychiatry, Assistance Publique-Hôpitaux de Paris, Bicêtre University Hospital, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
| | - R Calati
- INSERM U1061, University of Montpellier, FondaMental Foundation, Montpellier, France
| | - A Serretti
- Department of Biomedical and Neuromotor Science, University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy
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18
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Min YW, Rhee PL. The clinical potential of ramosetron in the treatment of irritable bowel syndrome with diarrhea (IBS-D). Therap Adv Gastroenterol 2015; 8:136-42. [PMID: 25949526 PMCID: PMC4416292 DOI: 10.1177/1756283x15572580] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent functional bowel disorder. Serotonin (5-HT) is known to play a physiological and pathophysiological role in the regulation of gastrointestinal function. In experimental studies, 5-HT3 receptor antagonists have been reported to slow colon transit, to blunt gastrocolonic reflex, and to reduce rectal sensitivity. Alosetron and cilansetron, potent and selective 5-HT3 receptor antagonists, have proven efficacy in the treatment of IBS with diarrhea (IBS-D). However, alosetron was voluntarily withdrawn due to postmarketing reports of ischemic colitis and complications of constipation, and cilansetron was never marketed. Currently alosetron is available under a risk management program for women with severe IBS-D. Ramosetron is another potent and selective 5-HT3 receptor antagonist, which has been marketed in Japan, South Korea, and Taiwan. In animal studies, ramosetron reduced defecation induced by corticotrophin-releasing hormone and had inhibitory effects on colonic nociception. In two randomized controlled studies including 957 patients with IBS-D, ramosetron increased monthly responder rates of patient-reported global assessment of IBS symptom relief compared with placebo. Ramosetron was also as effective as mebeverine in male patients with IBS-D. In a recent randomized controlled trial with 343 male patients with IBS-D, ramosetron has proved effective in improving stool consistency, relieving abdominal pain/discomfort, and improving health-related quality of life. Regarding safety, ramosetron is associated with a lower incidence of constipation compared with other 5-HT3 receptor antagonists and has not been associated with ischemic colitis. Although further large prospective studies are needed to assess whether ramosetron is effective for female patients with IBS-D and to evaluate its long-term safety, ramosetron appears to be one of the most promising agents for patients with IBS-D.
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Affiliation(s)
- Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea
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19
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Akhmedov VA. The development of functional gastrointestinal diseases: Genetic aspects. TERAPEVT ARKH 2015. [DOI: 10.17116/terarkh2015878119-123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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20
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Wouters MM, Lambrechts D, Knapp M, Cleynen I, Whorwell P, Agréus L, Dlugosz A, Schmidt PT, Halfvarson J, Simrén M, Ohlsson B, Karling P, Van Wanrooy S, Mondelaers S, Vermeire S, Lindberg G, Spiller R, Dukes G, D'Amato M, Boeckxstaens G. Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome. Gut 2014; 63:1103-11. [PMID: 24041540 DOI: 10.1136/gutjnl-2013-304570] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS. DESIGN 384 single nucleotide polymorphisms (SNPs) covering 270 genes were genotyped in an exploratory cohort (935 IBS patients, 639 controls). 33 SNPs with Puncorrected<0.05 were validated in an independent set of 497 patients and 887 controls. Genotype distributions of single SNPs were assessed using an additive genetic model in IBS and clinical subtypes, IBS-C and IBS-D, both in individual and combined cohorts. Trait anxiety (N=614 patients, 533 controls), lifetime depression (N=654 patients, 533 controls) and mRNA expression in rectal biopsies (N=22 patients, 29 controls) were correlated with SNP genotypes. RESULTS Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)). When combining both cohorts, the association of rs2349775 withstood post hoc correction for multiple testing in the IBS-D subgroup. Additionally, three SNPs in immune-related genes (rs1464510-LPP, rs1881457-IL13, rs2104286-IL2RA), one SNP in a neuronal gene (rs2349775-NXPH1) and two SNPs in epithelial genes (rs245051-SLC26A2, rs17837965-CDC42) were weakly associated with total-IBS (Puncorrected<0.05). At the functional level, rs1881457 increased IL13 mRNA levels, whereas anxiety and depression scores did not correlate with rs2349775-NXPH1. CONCLUSIONS Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with IBS-D and IBS-C, respectively, in two independent cohorts. Further studies are warranted to validate our findings and to determine the mechanisms underlying IBS pathophysiology.
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Affiliation(s)
- Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, Leuven University, Leuven, Belgium
| | - Michael Knapp
- Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Isabelle Cleynen
- Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
| | - Peter Whorwell
- Department of Medicine, University of Manchester, Manchester, UK
| | - Lars Agréus
- Centre for Family Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Aldona Dlugosz
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Jonas Halfvarson
- Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden
| | - Magnus Simrén
- Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden
| | - Bodil Ohlsson
- Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden
| | | | - Sander Van Wanrooy
- Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
| | - Stéphanie Mondelaers
- Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
| | - Severine Vermeire
- Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
| | - Greger Lindberg
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - George Dukes
- Academic DPU, GlaxoSmithKline, Research Triangle Par, North Carolina, USA
| | - Mauro D'Amato
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Guy Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
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Mulak A, Taché Y, Larauche M. Sex hormones in the modulation of irritable bowel syndrome. World J Gastroenterol 2014; 20:2433-2448. [PMID: 24627581 PMCID: PMC3949254 DOI: 10.3748/wjg.v20.i10.2433] [Citation(s) in RCA: 176] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 12/10/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of “microgenderome” related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.
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Zhang ZF, Duan ZJ, Wang LX, Yang D, Zhao G, Zhang L. The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies. BMC Gastroenterol 2014; 14:23. [PMID: 24512255 PMCID: PMC3926682 DOI: 10.1186/1471-230x-14-23] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 01/30/2014] [Indexed: 12/14/2022] Open
Abstract
Background The results of previous studies assessing the association between the 5-HTTLPR polymorphism of serotonin transporter gene and irritable bowel syndrome (IBS) are inconsistent. The aim of this study was to clarify the association between the 5-HTTLPR mutation and the presence of IBS and its subtypes with a meta-analysis of 25 studies. Methods A thorough search for case–control studies evaluating the association between the 5-HTTLPR polymorphism of serotonin transporter gene and the presence of IBS was carried out in four electronic databases. A meta-analysis was performed in accordance with the Cochrane Handbook for systemic reviews. Results A total of 25 articles with 3443 IBS cases and 3359 controls were included into our meta-analysis. No significant association was found between this polymorphism and IBS in all populations. Whereas the LL genotype was demonstrated to be a risk factor for constipation predominant IBS (IBS-C) development in the overall population (LL vs SS: OR = 1.570, 95% CI = 1.147-2.148, P = 0.005, Bon = 0.030; LL vs LS: OR = 1.658, 95% CI = 1.180-2.331, P = 0.004, Bon = 0.024; LL vs LS/SS: OR = 1.545, 95% CI = 1.187-2.012, P = 0.001, Bon = 0.006). In the analysis of different ethnicities, L allele and LL genotype were significantly associated with increased IBS-C risk in the East Asian population (L vs S: OR = 1.487, 95% CI = 1.139-1.941, P = 0.003, Bon = 0.018; LL vs SS: OR = 2.575, 95% CI = 1.741-3.808, P = 0.000, Bon = 0.000; LL vs LS: OR = 3.084, 95% CI = 2.017-4.715, P = 0.000, Bon = 0.000; LL vs LS/SS: OR = 2.759, 95% CI = 1.933-3.938, P = 0.000, Bon = 0.000), but not in the Caucasian population. Conclusions Different from the conclusions of the earlier meta-analyses, the 5-HTTLPR mutation affects IBS-C but not IBS-D and IBS-M development and this effect only exists in the East Asian population but not other populations.
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Affiliation(s)
| | - Zhi-Jun Duan
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000 Dalian, Liaoning province, China.
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Vaiopoulou A, Karamanolis G, Psaltopoulou T, Karatzias G, Gazouli M. Molecular basis of the irritable bowel syndrome. World J Gastroenterol 2014; 20:376-383. [PMID: 24574707 PMCID: PMC3923013 DOI: 10.3748/wjg.v20.i2.376] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional disorder characterized by abdominal pain, discomfort and bloating. The pathophysiology of IBS is poorly understood, but the presence of psychosocial basis is now known. There is an increasing number of publications supporting the role of genetics in IBS. Most of the variations are found in genes associated with the brain-gut axis, revealing the strong correlation of brain-gut axis and IBS. miRNAs, which play critical roles in physiological processes, are not well studied in IBS. However, so far there is found an involvement of alterations in miRNA expression or sequence, in IBS symptoms. IBS phenotype is affected by epigenetic alteration and environment. Changes in DNA and histone methylation are observed in patients who suffered childhood trauma or abuse, resulting in altered gene expression, such as the glucocorticoid receptor gene. Finally, diet is another factor associated with IBS, which may contribute to symptom onset. Certain foods may affect on bacterial metabolism and epigenetic modifications, predisposing to IBS.
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Farjadian S, Fakhraei B, Moeini M, Nasiri M, Fattahi MR. Serotonin transporter gene polymorphisms in Southwestern Iranian patients with irritable bowel syndrome. Arab J Gastroenterol 2013; 14:59-62. [PMID: 23820502 DOI: 10.1016/j.ajg.2013.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2013] [Revised: 02/16/2013] [Accepted: 03/10/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND STUDY AIMS Irritable bowel syndrome is a common chronic functional gastrointestinal disorder of unknown etiology. Serotonin is an important factor in sensory signaling in the brain-gut axis, which plays a key role in intestinal motility and secretion. Serotonin clearance is mediated by a specific protein called the serotonin reuptake transporter. Transcription activity of the serotonin transporter gene is affected by some polymorphisms in this gene. The aim of this study was to investigate the relationship between serotonin transporter gene polymorphisms and irritable bowel syndrome. PATIENTS/MATERIAL AND METHODS The 5-HTTLPR, rs25531 and STin2VNTR polymorphisms of the serotonin transporter gene were analyzed by PCR-based methods in 50 patients with irritable bowel syndrome and 100 healthy controls. RESULTS Serotonin transporter polymorphisms were similar in patients and healthy controls. There were no significant differences in allele or genotype frequencies between the two groups. CONCLUSION Our findings suggest that polymorphisms in the gene encoding for the serotonin transporter are not associated with irritable bowel syndrome. Interactions between environmental factors and predisposing genetic factors are important in the pathophysiology of irritable bowel syndrome, and further genetic and epigenetic research may provide novel insights into the mechanisms contributing to this disease.
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Affiliation(s)
- Shirin Farjadian
- Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
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Dai C, Zheng CQ, Jiang M. Letter: serotonin transporter gene polymorphisms and the irritable bowel syndrome. Aliment Pharmacol Ther 2013; 37:657-658. [PMID: 23406411 DOI: 10.1111/apt.12222] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 01/05/2013] [Indexed: 12/11/2022]
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Colucci R, Gambaccini D, Ghisu N, Rossi G, Costa F, Tuccori M, De Bortoli N, Fornai M, Antonioli L, Ricchiuti A, Mumolo MG, Marchi S, Blandizzi C, Bellini M. Influence of the serotonin transporter 5HTTLPR polymorphism on symptom severity in irritable bowel syndrome. PLoS One 2013; 8:e54831. [PMID: 23393559 PMCID: PMC3564922 DOI: 10.1371/journal.pone.0054831] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Accepted: 12/19/2012] [Indexed: 12/15/2022] Open
Abstract
5HTTLPR polymorphism of serotonin transporter yields short (S) and long (L) alleles. SS and LS genotypes are associated with reduced expression of serotonin transporter. This cross-sectional study investigated the association of 5HTTLPR with symptom severity of irritable bowel syndrome (IBS). Patients with IBS (Rome III) and healthy controls were included. Genomic DNA was extracted from saliva, and 5HTTLPR alleles were assessed by polymerase chain reaction. IBS symptom severity was evaluated by means of IBS-SSS questionnaire. Two hundreds and four IBS patients (159 females; mean age: 39.6±12.3 years; 106 with constipation: C-IBS; 98 with diarrhea: D-IBS) and 200 healthy controls (154 females; mean age: 40.4±15.8 years) were enrolled. The overall IBS-SSS value was higher in LS/SS than LL patients (319.0±71.5 versus 283.8±62.3; P = 0.0006). LS/SS patients had also higher values of abdominal pain (59.7±21.0 versus 51.0±18.8; P = 0.020) and bowel dissatisfaction (80.1±23.9 versus 70.5±22.8; P = 0.035). The overall IBS-SSS values in C-IBS and D-IBS patients were 317.2±68.3 and 296.1±71.4, respectively (P = 0.192), with significantly higher values for abdominal distension (65.0±24.4 versus 51.4±24.8; P = 0.0006), but not for bowel dissatisfaction (80.5±21.7 versus 72.9±25.7; P = 0.138). Frequencies of 5HTTLPR genotypes did not differ significantly when comparing IBS patients (overall or upon stratification in C-IBS and D-IBS) with healthy controls. In conclusion, the LS and SS genotypes are significantly correlated with IBS symptom severity, although their possible direct causal role remains to be proven. In addition, the present findings do not support an association of 5HTTLPR with IBS or its clinical presentation in terms of bowel habit predominance.
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Affiliation(s)
- Rocchina Colucci
- Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Dario Gambaccini
- Unit of Gastroenterology, Department of Translational Medicine, University of Pisa, Pisa, Italy
| | - Narcisa Ghisu
- Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giuseppe Rossi
- Unit of Epidemiology and Biostatistics, Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Francesco Costa
- Unit of Gastroenterology, Department of Translational Medicine, University of Pisa, Pisa, Italy
| | - Marco Tuccori
- Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nicola De Bortoli
- Unit of Gastroenterology, Department of Translational Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Angelo Ricchiuti
- Unit of Gastroenterology, Department of Translational Medicine, University of Pisa, Pisa, Italy
| | - Maria Gloria Mumolo
- Unit of Gastroenterology, Department of Translational Medicine, University of Pisa, Pisa, Italy
| | - Santino Marchi
- Unit of Gastroenterology, Department of Translational Medicine, University of Pisa, Pisa, Italy
| | - Corrado Blandizzi
- Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- * E-mail:
| | - Massimo Bellini
- Unit of Gastroenterology, Department of Translational Medicine, University of Pisa, Pisa, Italy
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Areeshi MY, Haque S, Panda AK, Mandal RK. A serotonin transporter gene (SLC6A4) polymorphism is associated with reduced risk of irritable bowel syndrome in American and Asian population: a meta-analysis. PLoS One 2013; 8:e75567. [PMID: 24069428 PMCID: PMC3777956 DOI: 10.1371/journal.pone.0075567] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 08/14/2013] [Indexed: 02/08/2023] Open
Abstract
AIM Association studies of serotonin transporter gene SLC6A4 I/S polymorphism and irritable bowel syndrome (IBS) have shown inconsistent and contradictory results among different populations. In the present study, meta-analysis was performed to evaluate the association between SLC6A4 I/S polymorphism and IBS susceptibility. METHODOLOGY Systemic assessment was performed for the published studies based on the association of SLC6A4 I/S polymorphism and IBS risk from PubMed (Medline), EMBASE search. A meta-analysis was done to appraise the said association. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for allele contrast, homozygous, heterozygous, dominant and recessive genetic model. RESULTS A total of twelve studies comprising 2068 IBS cases and 2076 controls were included in this meta-analysis. Overall, no significant results were obtained for S allele carrier (S vs. I: p=0.488; OR=1.073, 95% CI=0.879 to 1.311) Co-dominant (SS vs. II; p=0.587; OR=1.112, 95% CI=0.758 to 1.631), (IS vs. II; p=0.361; OR=0.878, 95% CI=0.665 to 1.160). Similarly, dominant (SS+IS vs. II: p=0.853; OR=0.974, 95% CI=0.736 to 1.288) and recessive (SS vs. II+IS: p=0.267; OR=1.172, 95% CI=0.886 to 1.522) genetic models did not demonstrate risk. In the subgroup population based analysis, reduced risks were found in American (IS vs. II: p=0.009; OR=0.685, 95% CI=0.516 to 0.908) and Asian (SS+IS vs. II; p=0.001; OR=0.116, 95% CI=0.068 to 0.197) population. However, no risk was observed in European population. CONCLUSIONS This investigation clearly demonstrates that SLC6A4 (Ins/Del) polymorphism is associated with reduced risk of IBS in American and Asian population. However, future well-designed studies with stratified case control and biological characterization will be needed to validate this finding.
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Affiliation(s)
- Mohammed Y. Areeshi
- Department of Medical Microbiology, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Shafiul Haque
- Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Aditya K. Panda
- Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, Odisha, India
| | - Raju K. Mandal
- Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
- * E-mail:
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Wang YM, Chang Y, Chang YY, Cheng J, Li J, Wang T, Zhang QY, Liang DC, Sun B, Wang BM. Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients. Neurogastroenterol Motil 2012; 24:560-5, e254-5. [PMID: 22435794 DOI: 10.1111/j.1365-2982.2012.01902.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The role of serotonin transporter (SERT) gene polymorphism in irritable bowel syndrome (IBS) has been demonstrated. However, the expression of SERT mRNA and proteins in the colonic mucosa with different 5-HTT gene-linked polymorphic region (5-HTTLPR) genotypes remains unknown. We examined SERT mRNA and protein levels in colon biopsies from patients with different 5-HTTLPR genotypes and evaluated the links between the polymorphism and the expression levels. METHODS Two hundred and fifty-four patients with IBS and 120 healthy subjects were studied. DNA samples were extracted from peripheral blood and genotyped by polymerase chain reaction (PCR). SERT mRNA and protein levels were evaluated by quantitative real time PCR and western blotting. The promoter efficiency of the serotonin transporter promoter (SERT-P) was evaluated with luciferase reporter system. KEY RESULTS The frequency of the L/L genotype in C-IBS group was significantly higher than that in the control and D-IBS. However, the S/S genotype in D-IBS was significantly higher than that in C-IBS. The transcriptional efficiency of the L/L genotype was significantly higher than that in the L/S and S/S genotype. Patients with the L/L genotype demonstrated increased production of the SERT protein when compared with L/S and S/S patients. The l variant increased SERT promoter activity by 2.43-fold when compared with the s variant. CONCLUSIONS & INFERENCES Polymorphism in the promoter region of the SERT gene can influence the expression of SERT mRNA and the levels of the SERT protein in the colonic mucosa, thereby playing a key role in motility-related symptoms of IBS patients.
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Affiliation(s)
- Y M Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University Hospital, Tianjin, China
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Camilleri M, Katzka DA. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1075-84. [PMID: 22403795 PMCID: PMC3362100 DOI: 10.1152/ajpgi.00537.2011] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 03/05/2012] [Indexed: 01/31/2023]
Abstract
The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, α(2)-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNFα, GNβ3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT(3) genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
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Morley AP, Narayanan M, Mines R, Molokhia A, Baxter S, Craig G, Lewis CM, Craig I. AVPR1A and SLC6A4 polymorphisms in choral singers and non-musicians: a gene association study. PLoS One 2012; 7:e31763. [PMID: 22384070 PMCID: PMC3285181 DOI: 10.1371/journal.pone.0031763] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 01/15/2012] [Indexed: 12/02/2022] Open
Abstract
Amateur choral singing is a common pastime and worthy of study, possibly conferring benefits to health and social behaviour. Participants might be expected to possess musical ability and share some behavioural characteristics. Polymorphisms in genes concerned with serotonergic neurotransmission are associated with both behaviour and musical aptitude. Those investigated previously include the variable number tandem repeats RS1, RS3 and AVR in the AVPR1A (arginine vasopressin receptor 1a) gene and STin2 in the SLC6A4 (solute carrier family 6 [neurotransmitter transporter, serotonin], member 4) gene, as well as the SLC6A4 promoter region polymorphism, 5-HTTLPR. We conducted a genetic association study on 523 participants to establish whether alleles at these polymorphisms occur more commonly in choral singers than in those not regularly participating in organised musical activity (non-musicians). We also analysed tagging single nucleotide polymorphisms (SNPs) for AVPR1A and SLC6A4 to determine whether other variants in these genes were associated with singer/non-musician status. At the STin2 polymorphism, overall association with singer/non-musician status was evident at P = 0.006. The 9-repeat (P = 0.04) and 12-repeat (P = 0.04) alleles were more common in singers and the 10-repeat allele less so (P = 0.009). Odds ratios were 0.73 (95% CI 0.57–0.94) for the 10-repeat allele and 2.47 (95% CI 0.88–6.94) for the rarer 9-repeat allele. No overall association was detected at P<0.05 between any other polymorphism and singer/non-musician status. Our null findings with respect to RS3, RS1 and AVR, polymorphisms associated with musical ability by other authors, suggest that choir membership may depend partly on factors other than musical ability. In a related musical project involving one participating choir, a new 40-part unaccompanied choral work, “Allele”, was composed and broadcast on national radio. In the piece, each singer's part incorporated their personal RS3 genotype.
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Affiliation(s)
- Andrew P Morley
- King's Health Partners Academic Health Sciences Centre, London, United Kingdom.
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Zhong L, Hou X. Pathophysiologic findings of irritable bowel syndrome in china. J Neurogastroenterol Motil 2012; 18:19-33. [PMID: 22323985 PMCID: PMC3271250 DOI: 10.5056/jnm.2012.18.1.19] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 12/14/2011] [Accepted: 12/22/2011] [Indexed: 01/30/2023] Open
Abstract
The mechanism of irritable bowel syndrome (IBS) is still incompletely understood in the world although large amount of investigations have been carried out on it. There are many studies on the pathophysiology of IBS in China, which has huge amount of population suffering from IBS with special ethnicity and culture, including Mainland China, Hong Kong and Taiwan. We collected the literatures to show the results and discuss whether there were any differences in the pathophysiologic findings between China and other countries, whether there were any differences among different subtypes and how the pathophysiology correlated with the manifestations of patients. Gene polymorphism, disturbances of gastrointestinal motility, visceral hypersensitivity, intestinal infection and inflammation, psychological disturbances, food hypersensitivity and intolerance, and altered gut microflora were reviewed in this paper. Some conflicting outcomes between China and other countries were noted although most of them were similar.
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Affiliation(s)
- Likun Zhong
- Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
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Markoutsaki T, Karantanos T, Gazouli M, Anagnou NP, Ladas SD, Karamanolis DG. Serotonin transporter and G protein beta 3 subunit gene polymorphisms in Greeks with irritable bowel syndrome. Dig Dis Sci 2011; 56:3276-3280. [PMID: 21559741 DOI: 10.1007/s10620-011-1726-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Accepted: 04/15/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Polymorphisms in the serotonin transporter (SERT) and G protein β3 subunit (GNB3) genes might contribute to the pathophysiology of irritable bowel syndrome (IBS). Association studies of SERT and GNB3 polymorphisms and IBS have shown diverse results among different populations, which might be due to subject composition differences. AIMS The aim of the study was to assess the potential association between SERT and GNB3 polymorphisms and IBS in Greeks. METHODS A total of 124 patients with IBS diagnosed according to the Rome III criteria and 238 healthy individuals were included in the study. SERT and GNB3 gene polymorphisms were genotyped using polymerase chain reaction-based methods. RESULTS It was shown that the frequencies of the SS genotype and S allele of the serotonin transporter polymorphism were significantly associated with IBS (P = 0.0314 and P = 0.019, respectively). TT genotype and T allele frequencies of G protein β3 subunit showed also significant difference between the IBS patients and healthy controls IBS (P = 0.0163 and P = 0.0001, respectively). None of the clinical symptoms analyzed was significantly associated with the polymorphisms tested. CONCLUSIONS The results suggest that SERT and GNB3 gene polymorphisms might be associated with irritable bowel syndrome predisposition in Greeks.
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Affiliation(s)
- T Markoutsaki
- 2nd Department of Gastroenterology, Evangelismos General Hospital, Athens, Greece
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Toyoshima F, Oshima T, Nakajima S, Sakurai J, Tanaka J, Tomita T, Hori K, Matsumoto T, Miwa H. Serotonin transporter gene polymorphism may be associated with functional dyspepsia in a Japanese population. BMC MEDICAL GENETICS 2011; 12:88. [PMID: 21714874 PMCID: PMC3142494 DOI: 10.1186/1471-2350-12-88] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Accepted: 06/29/2011] [Indexed: 12/16/2022]
Abstract
Background Although familial clustering of functional dyspepsia (FD) has been reported, the role of genetics in the susceptibility to FD is still not well understood. In the present study, the association between serotonin transporter (SERT) gene (SLC6A4) polymorphism and FD was explored. Methods Subjects were divided into either a postprandial distress syndrome (PDS) group or an epigastric pain syndrome (EPS) group according to the Rome III criteria. The healthy controls were those who had visited a hospital for an annual health check-up. The presence of the SLC6A4 promoter polymorphism, 5-hydroxytryptamin transporter gene linked polymorphic region (5-HTTLPR), was then evaluated, and logistic regression analysis was used to test all variables. Results The 5-HTTLPR genotype distribution was 448 SS, 174 SL, and 24 LL in controls and 30 SS, 20 SL, and 3 LL in FD subjects. No significant correlation was found between the 5-HTTLPR genotype and FD. When the genotypes and subtypes of FD were exploratory evaluated, the SL genotype was significantly associated with PDS [odds ratio (OR) = 2.24, 95% confidence interval (CI); 1.16-4.32, P = 0.034 after Bonferroni correction] compared to the SS genotype adjusted for sex and age. Comparison of the SS genotype with the SL/LL genotype also showed a significant association of genotype with PDS (OR = 2.32, 95% CI; 1.23-4.37, P = 0.009). Conclusion The present results suggest that 5-HTTLPR L allele may influence the susceptibility to PDS.
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Affiliation(s)
- Fumihiko Toyoshima
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
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Abstract
Irritable bowel syndrome (IBS) is a common disorder that has been shown to aggregate in families and to affect multiple generations, but not in a manner consistent with a major Mendelian effect. Relatives of an individual with IBS are 2 to 3 times as likely to have IBS, with both genders being affected. To date, more than 100 genetic variants in more than 60 genes from various pathways have been studied in a number of candidate gene studies, with several positive associations reported. These findings suggest that there may be distinct, as well as shared, molecular underpinnings for IBS and its subtypes.
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Affiliation(s)
- Yuri A Saito
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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Spiller RC. Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome. Curr Opin Pharmacol 2011; 11:68-74. [PMID: 21398180 DOI: 10.1016/j.coph.2011.02.005] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 02/13/2011] [Accepted: 02/14/2011] [Indexed: 12/18/2022]
Abstract
Irritable bowel syndrome, which affects 5-10% of the population includes around 25% with predominantly diarrhoea (IBS-D). Several lines of evidence suggest an increase in mucosal 5-HT availability in IBS-D including a decrease in the serotonin transporter (SERT) which is also seen following acute diverticulitis. 5-HT(3) receptor antagonists have proved effective in suppressing urgency, prolonging small and large bowel transit and relieving symptoms in IBS-D. Alosetron continues to be used under restricted availability without any serious morbidity despite ischemic colitis which occurs at a rate of <1/1000 patient year. Other agents such as ramosetron and ondansetron are still in use and have not been associated with ischemic colitis. 5-HT(3) receptor agonists stimulate intestinal motility, shorten transit times and in a pilot trial accelerated transit in patients with IBS-C.
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Affiliation(s)
- Robin C Spiller
- NIHR Biomedical Research Unit, Nottingham Digestive Diseases Centre, University Hospital, Nottingham NG7 2UH, United Kingdom.
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Kaemmerer E, Plum P, Klaus C, Weiskirchen R, Liedtke C, Adolf M, Schippers A, Wagner N, Reinartz A, Gassler N. Fatty acid binding receptors in intestinal physiology and pathophysiology. World J Gastrointest Pathophysiol 2010; 1:147-153. [PMID: 21607156 PMCID: PMC3097959 DOI: 10.4291/wjgp.v1.i5.147] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Revised: 11/26/2010] [Accepted: 12/03/2010] [Indexed: 02/06/2023] Open
Abstract
Free fatty acids are essential dietary components and recognized as important molecules in the maintenance of cellular homeostasis. In the last decade, the molecular pathways for free fatty acid sensing in the gastrointestinal tract have been further elucidated by molecular identification and functional characterization of fatty acid binding receptors. These sensing molecules belong to the family of G protein-coupled receptors. In the intestine, four important receptors have been described so far. They differ in molecular structure, ligand specificity, expression pattern, and functional properties. In this review, an overview of intestinal fatty acid binding receptors and their role in intestinal physiology and pathophysiology is given.
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Sanger GJ, Lin Chang, Bountra C, Houghton LA. Challenges and prospects for pharmacotherapy in functional gastrointestinal disorders. Therap Adv Gastroenterol 2010; 3:291-305. [PMID: 21180610 PMCID: PMC3002590 DOI: 10.1177/1756283x10369922] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Functional gastrointestinal disorders, such as irritable bowel syndrome and functional dyspepsia, are complex conditions with multiple factors contributing to their pathophysiology. As a consequence they are difficult to treat and have posed significant challenges to the pharmaceutical industry when trying to develop new and effective treatments. This review provides an overview of these difficulties and how the industry is reshaping its drug developmental strategies. It describes some of the more significant and encouraging advances that have occurred, and discusses how future research might embrace the opportunities provided by advances in genetic and in particular, epigenetic research.
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Affiliation(s)
- Gareth J. Sanger
- Neurogastroenterology Group, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK
| | - Lin Chang
- Center for Neurobiology of Stress, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, VAGLAHS, Los Angeles, CA, USA
| | - Chas Bountra
- Structural Genomics Consortium, Nuffield Dept of Clinical Medicine, University of Oxford, Oxford, UK
| | - Lesley A. Houghton
- Neurogastroenterology Unit, School of Translational Medicine-GI Sciences, University of Manchester, Southmoor Road, Manchester M23 9LT, UK
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