Jose J. ter Linde

Candidate genotypes associated with functional dyspepsia

Abstract  There is accumulating evidence of a genetic predisposition for developing a functional gastrointestinal (GI) disorder. Identification of the genetic factors may improve understanding of underlying pathophysiological mechanisms. We aimed to test the association of functional polymorphisms in genes involved in serotonergic signalling and G‐protein‐mediated signal transduction, both affecting gastroduodenal sensory and motor function, with functional dyspepsia (FD). FD patients, send to our tertiary referral centre, were studied (n = 112). Healthy controls (n = 336) free of GI symptoms were matched 1 : 3 for age and gender. Polymorphisms in genes encoding the serotonin receptor type three A subunit (HTR3A), the serotonin transporter (SERT) and the G‐protein β3 subunit (GNB3) were analysed. The FD patients displayed a higher prevalence of the T allele of the GNB3 C825T polymorphism compared to healthy controls (OR = 1.60, 95% CI: 1.03–2.49, P = 0.038). No association between FD and the genotype of the insertion/deletion polymorphism in the promoter of SERT (SERT‐P) or HTR3A C178T polymorphism was observed. Tertiary referral FD is associated with the 825T allele of the GNB3 gene. The increased signal transduction associated with this allele may contribute to the abnormalities in gastroduodenal sensory and motor function observed in FD.

SERT and TPH-1 mRNA expression are reduced in irritable bowel syndrome patients regardless of visceral sensitivity state in large intestine.

Colorectal visceral hypersensitivity has been demonstrated in a subset of irritable bowel syndrome (IBS) patients. Serine protease and serotonergic signaling modulate gastrointestinal visceral sensitivity. We evaluated whether altered mucosal serine protease and serotonergic pathway components are related to rectal visceral hypersensitivity in IBS patients. Colorectal mucosal biopsies of 23 IBS patients and 15 controls were collected. Gene transcripts of protease-activated receptor (PAR)-2, trypsinogen IV, tryptophan hydroxylase (TPH)-1, and serotonin reuptake transporter (SERT) were quantified using real-time polymerase chain reaction. Substance P and 5-HT contents were measured by ELISA. The number of enterochromaffin cells, mast cells, and intraepithelial lymphocytes was determined using immunohistochemistry. Rectal visceral sensitivity was determined in IBS patients using barostat programmed for phasic ascending distension. Rectal hypersensitivity (+) and (-) IBS patients showed lower TPH-1 and SERT mRNA levels in the rectum compared with controls (P ≤ 0.05). Rectal hypersensitivity (+) IBS patients (n = 12) showed lower TPH-1 mRNA level in the sigmoid compared with controls (P = 0.015). No significant differences were observed in PAR-2 and trypsinogen IV expression between controls and IBS patients. Rectal substance P content was increased in IBS patients compared with controls (P = 0.045). No significant differences were found in transcript levels, cell counts, and substance P and 5-HT contents between rectal hypersensitivity (+) and (-) IBS patients. In conclusion, regardless of visceral hypersensitivity state, several serotonergic signaling components are altered in IBS patients.

Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia

BackgroundThe association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity.MethodsData from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia.ResultsHTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90).ConclusionsThe HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT3 mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.

Different characteristics of patients with gastro-oesophageal reflux disease on their path through healthcare: a population follow-up study.

Background Only a minority of patients with gastro-oesophageal reflux symptoms (GORS) seek medical advice. Little is known about patient characteristics associated with consultation in primary care and referral to secondary care. Aims and methods We compared the characteristics of patients with GORS in the general population, those who consulted their general practitioner (GP) and those referred to secondary care for upper endoscopy. We aimed to identify differences between patients with short term (<90 days) and chronic symptoms, and differences between patients with symptoms in primary and secondary care. The study was performed in a primary care based prospective dynamic population. Results In total, 16% of 7237 adult patients were identified with GORS. Twenty-five percent of these patients consulted the GP, of whom 40% were referred for endoscopy. Patients with chronic GORS were older, had a higher body mass index, were more often referred for upper endoscopy (all P<0.001) and more frequently had relevant findings during endoscopy (oesophagitis: 50% and Barretts oesophagus: 10%). Patients referred for upper endoscopy were older than nonreferred patients (P<0.001). Conclusion Only a minority of people with GORS visit their GP. After consulting referral for endoscopy occurs relatively often. Underlying endoscopic abnormalities are frequently found in patients with chronic GORS.