Epigenetic modification of serotonin transporter gene in the gastric mucosa of functional dyspepsia

Background / Aim: Neurochemical serotonin (5-HT) has a role in the gastrointestinal motor and sensory functions. 5-HT level is regulated by the serotonin transporter (5-HTT; SLC6A4). 5-HTT expression may be regulated by epigenetics. DNA methylation of SLC6A4 gene in the gastric mucosa of functional dyspepsia (FD) was evaluated. Methods: Gastric biopsies were obtained from 79 FD and 78 asymptomatic controls. Bisulfite pyrosequencing were performed to determine the methylation status of promoter CpG islands (PCGIs), promoter non-CpG islands (PNCGIs) and gene body non-CpG islands (NPNCGIs) in the SLC6A4 gene. Gene expression was examined by real-time PCR. Results: Average methylation of PCGI was lower in FD compared to controls (4.5+/-0.3% vs. 5.7+/-0.5%, p=0.04). Conversely, methylation of NPNCGI was higher in FD compared to the controls (62.9+/-1.6% vs. 58.0+/-1.6%, p=0.03). Bisulfite sequencing confirmed FD with lower methylation in PCGI and PNCGI presents wide spread of hypo methylation around the promoter. The same patients also presented hyper methylation around the NPNCGI. Regarding the Rome III, lower methylation in PNCGIs was closely associated with PDS (p=0.01), while higher methylation in NPNCGIs was prominent in EPS (p=0.017). Methylation of SLC6A4 was inversely correlated with SLC6A4 mRNA level in FD. Conclusions: Epigenetic modification of serotonin transporter gene in the gastric mucosa may have a role in FD. A role of epigenetics for developing FD needs to be further evaluated.