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Multicenter Study
. 2022 Jun 7;28(21):2334-2349.
doi: 10.3748/wjg.v28.i21.2334.

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

Sabrina Berens  1 , Yuanjun Dong  2 , Nikola Fritz  2 , Jutta Walstab  3 , Mauro D'Amato  4 , Tenghao Zheng  5 , Verena Wahl  2 , Felix Boekstegers  6 , Justo Lorenzo Bermejo  6 , Cristina Martinez  2 , Stefanie Schmitteckert  2 , Egbert Clevers  7 , Felicitas Engel  8 , Annika Gauss  9 , Wolfgang Herzog  10 , Robin Spiller  11 , Miriam Goebel-Stengel  12 , Hubert Mönnikes  13 , Viola Andresen  14 , Frieling Thomas  15 , Jutta Keller  16 , Christian Pehl  17 , Christoph Stein-Thöringer  18 , Gerard Clarke  19 , Timothy G Dinan  19 , Eamonn M Quigley  20 , Gregory Sayuk  21 , Magnus Simrén  22 , Jonas Tesarz  8 , Gudrun Rappold  2 , Lukas van Oudenhove  23 , Rainer Schaefert  8 , Beate Niesler  24
Affiliations
Multicenter Study

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

Sabrina Berens et al. World J Gastroenterol. .

Abstract

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 (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 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.

Keywords: 5-HT3 receptor subunit gene polymorphisms; Anxiety; Depression; Irritable bowel syndrome; Single-nucleotide polymorphism score; Somatization.

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Conflict of interest statement

Conflict-of-interest statement: APC Microbiome Ireland has conducted studies in collaboration with several companies, including GSK, Pfizer, Cremo, Suntory, Wyeth, Mead Johnson, Nutricia, 4D Pharma, and DuPont. Dinan TG has been an invited speaker at meetings organized by Servier, Lundbeck, Janssen, and AstraZeneca and has received research funding from Mead Johnson, Cremo, Suntory Wellness, Nutricia, and 4D Pharma. Clarke G has been an invited speaker at meetings organized by Janssen and is receipt of research funding from Pharmavite. The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this report.

Figures

Figure 1
Figure 1
Recruitment strategy. IBS: Irritable bowel syndrome.
Figure 2
Figure 2
Comparative analysis of 5-HT3AC 163N (major allele homozygous), 5-HT3AC 163K (minor allele homozygous), and 5-HT3AC 163K/163N (heterozygous) receptors. A: Radioligand-binding studies Saturation experiments were performed in membranes of HEK293 cells transiently expressing different 5-HT3 subunit combinations in triplicate with six increasing concentrations of [3H]GR65630 (0.02-1.5 nmol/L); Kd values were 0.07 ± 0.01 for 5-HT3AC 163N; 0.08 ± 0.01 for 5-HT3AC 163K, and 0.07 ± 0.01 for 5-HT3AC 163K/163N. n = 6 experiments; B: Concentration response curves were assessed in a calcium influx assay (aequorin assay) in HEK293 cells transiently transfected with different 5-HT3 subunit combinations in quadruplicate with seven increasing concentrations of 5-HT. pEC50 values were as follows: 68 ± 0.03 for 5-HT3AC 163N 5 and 5.66 ± 0.02 for 5-HT3AC 163K; C: Respective maximal calcium influx values (Emax) evoked by 5-HT (10 μmol/L). Data are expressed as percentages of the Emax of the heteromeric 5-HT3AC 163N receptor (% of control), n = 8 experiments. Bars represent mean ± SE. bP < 0.01 from ANOVA followed by Dunnett’s post-test or unpaired Student’s test for comparison of only two groups.
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