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.

Genetics of irritable bowel syndrome: shifting gear via biobank-scale studies

“…2a). Many studies have tested IBS risk associations with single-nucleotide polymorphisms (SNPs) in genes of 5-HT synthesis (tryptophan hydroxylase 1 and 2, encoded by TPH1 and TPH2, respectively), signalling (multiple 5-HT receptors; HTR3A, HTR3C, HTR3E and HTR4), and transport reuptake (SLC6A4 coding for the SERT transporter) [23][24][25][26][27][28][29][30][31][32] . In addition, small pharmacogenomic studies investigated some of these genes in relation to the response to pharmacotherapy (for example, alosetron (5-HT antagonist), tegaserod (5-HT agonist) and SLC6A4; ondansetron (5-HT antagonist) and HTR3C) and amygdala activation (HTR3A) in patients with IBS 26,28,30,33 .…”

Temporal Relationships Between Abdominal Pain, Psychological Distress and Coping in Patients With IBS – A Time Series Approach

“…A possible upper-level mechanism linking IBS with comorbid disorders could be a genetic alteration of serotonin reuptake receptors in some patients with IBS ( 10 – 12 ). Some of these alterations can affect bowel motility and have been shown to be associated with depression and anxiety ( 10 ).…”

Identification of gene candidates associated with Irritable bowel syndrome

“…11 The next selected polymorphisms belongs to the dopamine neurotransmitter system, which, together with serotonin neurotransmitter system is considered to play very important role in the aetiology of IBS. 12,13 The genetic variant in the dopamine neurotransmitter system is DAT (dopamine transporter) gene, located on the chromosome 5 at the p15.3. This polymorphic variant is a polymorphism of variable number of tandem repeats (VNTR) with 3-11 repeats, but the most common polymorphisms are 9 (440 bp) and 10 (480 bp).…”