Candidate genes and sensory functions in health and irritable bowel syndrome

Abstract

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (GI) function; these effects are mediated through G protein transduction. Candidate genetic variations in ADR-SER were significantly associated with somatic scores in irritable bowel syndrome (IBS) and gastric emptying but not small bowel or colonic transit. Our aim was to assess whether candidate ADR-SER genes are associated with motor and sensory GI functions in IBS and subgroups on the basis of bowel dysfunction. In 122 patients with IBS and 39 healthy controls, we assessed gastrointestinal somatic symptoms and affect by validated questionnaires. We measured: gastric volume (GV), maximum tolerated volume, rectal compliance, sensation thresholds and ratings, and genetic variations including alpha2A (C-1291G), alpha2C (Del 332-325), GNbeta3 (C825T), and 5-HTTLPR. Demographics and genotype distributions were similar in the patients with IBS subgrouped on bowel function. There were significant associations between 5-HTTLPR SS genotype and absence of IBS symptoms and between 5-HTTLPR LS/SS genotype and increased rectal compliance and increased pain ratings, particularly at 12 and 24 mmHg distensions. GNbeta3 was associated only with fasting GV; we did not detect associations between alpha2A genotype and the gastrointestinal sensory or motor functions tested. We concluded that 5-HTTLPR LS/SS genotype is associated with both increased pain sensation and increased rectal compliance though the latter effect is unlikely to contribute to increased pain sensation ratings with LS/SS genotype. The data suggest the hypotheses that the endophenotype of visceral hypersensitivity in IBS may be partly related to genetic factors, and the association of GNbeta3 with fasting GV may explain, in part, the reported association of GNbeta3 with dyspepsia.

Figures

Fig. 1.

Experimental design for measuring rectal compliance and sensation using ascending method of limits and random-order phasic distensions, respectively. Anxiety/depression sensory ratings were recorded on each day of testing. VAS, visual analog scales; BOP, baseline operating pressure.

Fig. 2.

Association of GNβ3 genotype with gastric volumes. After adjusting for age, body mass index (BMI), hospital anxiety and depression scale score, somatization, and group [irritable bowel syndrome (IBS) vs. health], fasting gastric volume is significantly associated (P = 0.03), and delta gastric volume borderline is significantly associated (P = 0.095). PP, postprandial.

Fig. 3.

Rectal compliance in health and IBS on the basis of SLC6A4 gene. The LS/SS genotype is associated with higher compliance (lower Pr1/2, P = 0.051). Data show least square means adjusted for age, BMI, somatization, and group (health vs. IBS).

Fig. 4.

Association of SLC6A4 genotype with pain sensation ratings at the different levels of distension (P = 0.052 for overall test across all 4 distension levels); note that the LL genotype is associated with lower pain sensation ratings especially with 12 and 24 mmHg (above BOP) distensions.