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.
Highlights
Accumulating evidence has shown that irritable bowel syndrome (IBS) is not just a functional gastrointestinal (GI) disorder, but rather represents a prototypical gut-brain disorder.[1,2] Irritable bowel syndrome (IBS) patients present with abdominal pain and variable alterations in bowel habits, which define the subtype of IBS
Identified single nucleotide polymorphisms (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
We have discovered a novel, functionally relevant cis-regulatory promoter haplotype in the SLC6A4 gene that is associated with IBS-C in females
Summary
Accumulating evidence has shown that irritable bowel syndrome (IBS) is not just a functional gastrointestinal (GI) disorder, but rather represents a prototypical gut-brain disorder.[1,2] IBS patients present with abdominal pain and variable alterations in bowel habits, which define the subtype of IBS. Serotonin metabolism is altered in IBS, and normalizing serotonin levels can ameliorate IBS symptoms.[2,21] Studies have revealed variable results regarding levels of 5-HT and its metabolites in IBS,15,22-25 but SERT expression was consistently found reduced in GI tissues of IBS patients, which supports findings of increased 5-HT in the tissue or blood.[22,23] How genetic factors affect 5-HT in IBS is still poorly understood. Unravelling these genetic mechanisms may help to develop effective, individualized treatment strategies for IBS. The genotype-phenotype correlations revealed the functional consequences of the identified SNPs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
