An exploratory study of the association of adrenergic and serotonergic genotype and gastrointestinal motor functions

Abstract

Adrenergic and serotonergic mechanisms alter human gut motor functions. Genotype variation influences phenotype. Our aim was to test the hypothesis that variation in genes that control these functions is associated with gastrointestinal (GI) motor functions in humans with functional GI disorders (FGID). A database of 251 people was assembled by combining genotype data with measurements of gut transit and gastric volumes. Genetic variations evaluated were: alpha(2A) adrenergic (C-1291G), alpha(2C) (Del 332-325), 5-HT transporter (SLC6A4) and GNbeta3 (C825T). We sought associations between motor function or disease groups and genotypes, adjusting for age, gender and body mass index. Among 251 participants, 82 were healthy, 20 with irritable bowel syndrome (IBS) with mixed bowel habit, 49 with constipation-predominant IBS, 67 with diarrhoea-predominant IBS and 33 with functional dyspepsia. For all candidate genes, there was no significant association between motor function and wildtype vs non-wildtype gene status. There were significant interactions between genotype and motility phenotype, specifically GNbeta3 and alpha(2A) and gastric emptying at 4 h. Borderline associations were noted for SCL6A4 and alpha(2A) and postprandial gastric volume, and for alpha(2C) and gastric emptying at 2 h. We conclude that genotype variation may affect gastric motor functions in different FGID phenotypes. However, these candidate genes account for only a limited amount of the variance in gastric function of patients with FGID.

Candidate genes and sensory functions in health and irritable bowel syndrome

“…In a previous study (22), we also observed significant association between GN␤3 genotype and gastric emptying of solids at 4 h. The physiological factors that are significantly associated with the development of postprandial symptoms in dyspepsia are fasting gastric volume and accelerated gastric emptying at 1 h and delayed gastric emptying at 4 h (18). Together with the previous study (22), our present observations on the association of GN␤3 genotype and fasting gastric volume are consistent with the hypothesis that the epidemiological association of GN␤3 genotype with dyspepsia may be related to an association with abnormal gastric functions.…”

“…We have previously observed associations of the same genetic variations with gastric emptying in 251 participants (60 male and 191 female): 82 healthy, 20 patients with IBS with mixed bowel habit, 49 IBS-C, 67 IBS-D, and 33 functional dyspepsia (22). Those participants were selected from a database of people who had undergone gastrointestinal motility tests.…”

“…Thus it is conceivable that genetic variation in G proteins may influence the effects of neurotransmitters including norepinephrine and serotonin. Holtmann et al (22) observed an association between GN␤3 genotype and dyspepsia though the association with a variety of functional gastrointestinal disorders was not confirmed (1).…”

“…In a recently published study of 251 patients with dyspepsia or IBS or in healthy states, associations were demonstrated between candidate genes affecting adrenergic and serotonergic functions and gastric emptying or accommodation but not with small bowel or colonic transit (22).…”

Irritable bowel syndrome: new and emerging treatments

“…Pharmacotherapy for IBS-D: serotonin receptor antagonists Because more than 95% of the body's serotonin is located in the gastrointestinal tract and 5-HT 3 and 5-HT 4 receptor manipulation has been shown to alter gastrointestinal transit (for example, with alosetron and tegaserod), [108][109][110] serotonin is a viable therapeutic target. A randomized crossover trial published in 2013 assessed whether ondansetron, a 5HT 3 receptor antagonist traditionally used for nausea and vomiting, would be useful because of its constipating effect.…”