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The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

ABSTRACT: Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

SUBMITTER: Mohr S

PROVIDER: S-EPMC8358858 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The serotonin transporter polymorphism rs25531 is associated with irritable bowel syndrome.

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| S-EPMC2937164 | biostudies-literature

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| S-EPMC5037082 | biostudies-literature

Association study of serotonin transporter SLC6A4 gene with Chinese Han irritable bowel syndrome.

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| S-EPMC3879322 | biostudies-literature

Rare Variants of the Serotonin Transporter Are Associated With Psychiatric Comorbidity in Irritable Bowel Syndrome.

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Serotonin Transporter Gene (SLC6A4) Polymorphism and Mucosal Serotonin Levels in Southeastern Iranian Patients with Irritable Bowel Syndrome.

Project description: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.

| S-EPMC5308131 | biostudies-other

Influence of the serotonin transporter 5HTTLPR polymorphism on symptom severity in irritable bowel syndrome.

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| S-EPMC3564922 | biostudies-other

The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies.

Project description:BackgroundThe 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.MethodsA 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.ResultsA 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.ConclusionsDifferent 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.

| S-EPMC3926682 | biostudies-literature

Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women.

Project description:Background and aimsSerotonin (5-hydroxtryptamine, 5-HT) is an important factor in gut function, playing key roles in intestinal peristalsis and secretion, and in sensory signalling in the brain-gut axis. Removal from its sites of action is mediated by a specific protein called the serotonin reuptake transporter (SERT or 5-HTT). Polymorphisms in the promoter region of the SERT gene have effects on transcriptional activity, resulting in altered 5-HT reuptake efficiency. It has been speculated that such functional polymorphisms may underlie disturbance in gut function in individuals suffering with disorders such as irritable bowel syndrome (IBS). The aim of this study was to assess the potential association between SERT polymorphisms and the diarrhoea predominant IBS (dIBS) phenotype.SubjectsA total of 194 North American Caucasian female dIBS patients and 448 female Caucasian controls were subjected to genotyping.MethodsLeucocyte DNA of all subjects was analysed by polymerase chain reaction based technologies for nine SERT polymorphisms, including the insertion/deletion polymorphism in the promoter (SERT-P) and the variable tandem repeat in intron 2. Statistical analysis was performed to assess association of any SERT polymorphism allele with the dIBS phenotype.ResultsA strong genotypic association was observed between the SERT-P deletion/deletion genotype and the dIBS phenotype (p = 3.07x10(-5); n = 194). None of the other polymorphisms analysed was significantly associated with the presence of disease.ConclusionsSignificant association was observed between dIBS and the SERT-P deletion/deletion genotype, suggesting that the serotonin transporter is a potential candidate gene for dIBS in women.

| S-EPMC1774243 | biostudies-literature

MicroRNA-200a Targets Cannabinoid Receptor 1 and Serotonin Transporter to Increase Visceral Hyperalgesia in Diarrhea-predominant Irritable Bowel Syndrome Rats.

Project description:Background/aimsMicroRNAs (miRNAs) were reported to be responsible for intestinal permeability in diarrhea-predominant irritable bowel syndrome (IBS-D) rats in our previous study. However, whether and how miRNAs regulate visceral hypersensitivity in IBS-D remains largely unknown.MethodsWe established the IBS-D rat model and evaluated it using the nociceptive visceral hypersensitivity test, myeloperoxidase activity assay, restraint stress-induced defecation, and electromyographic (EMG) activity. The distal colon was subjected to miRNA microarray analysis followed by isolation and culture of colonic epithelial cells (CECs). Bioinformatic analysis and further experiments, including dual luciferase assays, quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay, were used to detect the expression of miRNAs and how it regulates visceral hypersensitivity in IBS-D rats.ResultsThe IBS-D rat model was successfully established. A total of 24 miRNAs were differentially expressed in the distal colon of IBS-D rats; 9 were upregulated and 15 were downregulated. Among them, the most significant upregulation was miR-200a, accompanied by downregulation of cannabinoid receptor 1 (CNR1) and serotonin transporter (SERT). MiR-200a mimic markedly inhibited the expression of CNR1/SERT. Bioinformatic analysis and luciferase assay confirmed that CNR1/SERT are direct targets of miR-200a. Rescue experiments that overexpressed CNR1/SERT significantly abolished the inhibitory effect of miR-200a on the IBS-D rats CECs.ConclusionsThis study suggests that miR-200a could induce visceral hyperalgesia by targeting the downregulation of CNR1 and SERT, aggravating or leading to the development and progression of IBS-D. MiR-200a may be a regulator of visceral hypersensitivity, which provides potential targets for the treatment of IBS-D.

| S-EPMC6175558 | biostudies-literature

Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis.

Project description:Background & aimsSodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C).MethodsIn a double-blind placebo-controlled study, 36 female patients with IBS-C were randomized to treatment with delayed-release oral formulations of placebo, 500 mg CDC, or 1000 mg CDC for 4 days. We assessed gastrointestinal and colonic transit, stool characteristics, and associations of transit with fasting serum 7αC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis) levels. Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in the 36 patients with IBS-C and 57 healthy volunteers to assess genetic influence on effects of CDC on transit.ResultsOverall colonic transit and ascending colon emptying (AC t(½)) were significantly accelerated in the CDC group compared with placebo (P = .005 and P = .028, respectively). Looser stool consistency (P = .003), increased stool frequency (P = .018), and greater ease of passage (P = .024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (P = .01). Fasting serum 7αC4 (but not FGF19) was positively associated with colonic transit (r(s) = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t(½) in response to CDC (uncorrected P = .015); αKlothoβ variant showed a gene-by-treatment interaction based on patient subgroup (uncorrected P = .0088).ConclusionsCDC accelerates colonic transit and improves bowel function in female patients with IBS-C. The rate of bile acid synthesis influences colonic transit. Genetic variation in negative feedback inhibition of bile acid synthesis may affect CDC-mediated acceleration of colonic transit.

| S-EPMC3189402 | biostudies-literature

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