In the present study, the prevalence of the 5-HTTLPR polymorphism was examined in dyspeptic patients in a Japanese population. Although the power was not enough for the analysis and the data are preliminary, the 5-HTTLPR L allele may be associated with an increased risk of PDS. Camilleri et al. and van Lelyveld et al. reported that the 5-HTTLPR polymorphism was not associated with dyspepsia in a population in the US and the Netherlands [33, 34]. The SERT mRNA expression in the gastric specimens of pediatric age FD patients was not significantly different compared with healthy controls . These contrasting observations may be explained by differences in the genotypic composition of populations in different countries with different racial groups. In fact, the frequency of the LL subtype is lower in the Japanese population than in Caucasian populations [35, 36]. In addition, the definition of FD or sample selection may also affect the outcome. Moreover, the effect of type II error cannot be excluded in relatively small sample sizes. Another limitation of this study was that the ages were different in the groups. However, age adjustment was performed in genotype analysis using logistic regression.
The SERT is the target of selective serotonin re-uptake inhibitors (SSRI), which are widely used as antidepressants. Although SSRIs have been reported to have a benefit in IBS , few trials have focused on FD treatment. Any evidence of effectiveness is weak to nonexistent. Wu et al. conducted an open clinical trial with 40 FD patients. They reported that fluoxetine improved symptom scores in depressive FD patients . Van Kerkhoven et al. conducted a randomized controlled trial with venlafaxine in 160 FD patients and showed no significant difference compared with placebo .
The results of the present study suggest the hypothesis that the 5-HTTLPR L allele may be associated with PDS. Based on in vitro studies of 5-HTTLPR polymorphism function, excessive transcription of SERT in 5-HTTLPR L allele would be expected to lead to higher 5-HT reuptake activity and decreased levels of 5-HT in the synaptic cleft , which in turn might result in decreased gut motility and secretion, subsequently causing postprandial fullness and early satiety, which are PDS symptoms. Actually after excluding subjects with both EPS and PDS, the association of SL genotype for the development of PDS was stronger (data not shown). However, the power was too small to conclude this from the present study. Furthermore, multiple testing may also affect the results. Therefore, we cannot exclude the effect of type I error.
The secreted 5-HT affects at least 30 subtypes of 7 main subclasses of serotonergic receptors that cause various effects on the gut or brain. There are several reports about the association between specific serotonergic receptors and dyspepsia. We have reported that the 5HT1A agonist tandospirone improved abdominal symptom scores, including upper abdominal pain and discomfort . On the other hand, Tack et al. reported that a 5HT1A agonist failed to improve symptoms, visceral hypersensitivity, or gastric accommodation compared with placebo . Boeckxstaens et al. also reported that a 5HT1A agonist had no effect on gastric fundus distension-evoked dyspeptic symptoms in healthy volunteers . Talley et al. reported that alosetron, a 5HT3 antagonist, had potential benefit in relieving functional dyspepsia symptoms compared to placebo . Maxton et al. and Kuo et al. also reported the effectiveness of alosetron for FD symptoms [45, 46]. In addition, Vakil et al. reported in their meta-analysis that tegaserod, a 5HT4 agonist, showed significant benefit in dysmotility, as occurs in FD .
Some reports seem to support our hypothesis, but there are several conflicting results. Therefore, the role of SERT functional differences in the gut is still unclear. The physiological effects on gut function of 5-HTTLPR polymorphism have been investigated in a report concerning IBS. However, there are many conflicting results .
Some studies have reported a sex relation in 5-HTTLPR polymorphism. Yeo et al. reported a significant association between D-IBS and 5-HTTLPR SS genotype in females . A similar result for anxiety traits was reported by Mizuno et al. Females with the L/S genotype showed higher anxiety scores than males . However, the sample size of this study was too small to conclude that there was a sex difference.