Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study.

Eamonn M Quigley, Hubert Mönnikes, Viola Andresen, Frieling Thomas, Jutta Keller, Christian Pehl, Christoph Stein-Thöringer, Gerard Clarke, Timothy G Dinan, Miriam Goebel-Stengel, Gregory Sayuk, Magnus Simrén, Jonas Tesarz, Gudrun Rappold, Lukas van Oudenhove, Rainer Schaefert, Beate Niesler, Sabrina Berens, Robin Spiller, Wolfgang Herzog, Annika Gauss, Felicitas Engel, Egbert Clevers, Stefanie Schmitteckert, Cristina Martinez, Justo Lorenzo Bermejo, Felix Boekstegers, Verena Wahl, Tenghao Zheng, Mauro D'Amato, Jutta Walstab, Nikola Fritz, Yuanjun Dong

Journal: World journal of gastroenterology 2022;28(21):2334-2349

PMID: 35800179

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Abstract

BACKGROUND

Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit () genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS).

AIM

To assess the association of polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS.

METHODS

In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - c.-42C>T, c.386A>C, c.489C>A, and c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of c.489C>A was tested by radioligand-binding and calcium influx assays.

RESULTS

Depressive and anxiety symptoms significantly worsened with increasing numbers of minor c.489C>A alleles in the dominant model ( = 7.475, = 0.006; = 6.535, = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score ( = 7.710, = 0.006) in IBS. The potential relevance of the SNP was corroborated, showing changes in the expression level of 5-HTAC variant receptors.

CONCLUSION

We have provided the first evidence that c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

Address: Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg 69120, Germany.; Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany.; Department of Human Molecular Genetics, University of Heidelberg, Heidelberg 69120, Germany.; Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio 48160, Spain.; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden.; Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany.; Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven 3000, Belgium.; Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany.; Department of Gastroenterology, Infectious Diseases and Intoxications, University of Heidelberg, Heidelberg 69120, Germany.; Department of General Internal Medicine and Psychosomatics, Heidelberg University, Heidelberg 69120, Germany.; Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2QL, United Kingdom.; Helios Klinikum Rottweil, Rottweil 78628, Germany.; Department of Medicine, Institute of Neurogastroenterology (H.M.), Martin-Luther-Hospital, Belin 14193, Germany.; Israelitisches Krankenhaus in Hamburg, Hamburg 22297, Germany.; Internal Medicine II, Helios Klinikum Krefeld, Krefeld 47805, Germany.; Israelitisches Krankenhaus Hamburg, Hamburg 22297, Ghana.; Krankenhaus Vilsbiburg, Vilsbiburg 84137, Germany.; Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.; Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland.; Medicine in Digestive Disorders, Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist, Houston, TX 77030, United States.; Division of Gastroenterology, Washington University School of Medicine, Department of Psychiatry, School of Medicine, John Cochran Veteran Affairs Medical Center, St. Louis, MO 63110, United States.; Department of Internal Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg SE-41685, Sweden.; Cognitive and Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03748, United States.; Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany.

DOI: 10.3748/wjg.v28.i21.2334

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MeSH Terms: Alleles, Humans, Irritable Bowel Syndrome, Polymorphism, Single Nucleotide, Receptors, Serotonin, 5-HT3, Retrospective Studies, Serotonin