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

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

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BACKGROUND Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) 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 HTR3 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 - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E 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 HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. 

RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (Fdepressive = 7.475, Pdepressive = 0.006; Fanxiety = 6.535, Panxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. 

CONCLUSION We have provided the first evidence that HTR3C 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.

Original languageEnglish
Pages (from-to)2334-2349
Number of pages16
JournalWorld Journal of Gastroenterology
Issue number21
Publication statusPublished - 7 Jun 2022
Externally publishedYes


  • 5-HT3 receptor subunit gene polymorphisms
  • Anxiety
  • Depression
  • Irritable bowel syndrome
  • Single-nucleotide polymorphism score
  • Somatization

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