Candidate genes and sensory functions in health and irritable bowel syndrome

Abstract

Zinsmeister AR. Candidate genes and sensory functions in health and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 295: 219 -225, 2008. First published May 29, 2008 doi:10.1152/ajpgi.90202.2008.-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 ␣2A (C-1291G), ␣2C (Del 332-325), GN␤3 (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. GN␤3 was associated only with fasting GV; we did not detect associations between ␣2A 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 GN␤3 with fasting GV may explain, in part, the reported association of GN␤3 with dyspepsia. adrenergic; serotonergic; GN␤3; SLC6A4; G protein; receptor ADRENERGIC MECHANISMS alter gastrointestinal reflexes involved in intestinal propulsion, coordinated motor activity in the small bowel and colon, and gastrointestinal tone and fluid secretion (12,46). Norepinephrine is also involved in control of pain including supraspinal inhibition of pain, e.g., due to a change in the behavioral state (37) including stress, which contributes to gut motility disorders (10).Among ␣2 receptors, the ␣2A subtype appears to be critically important for control of motor functions, such as gastrointestinal transit in mice (40) and colonic circular smooth muscle in canine colon (47). The ␣2 receptor agonist, clonidine, inhibits gastric and colonic tone, phasic contractility, and sensation in the rectum and colon in response to balloon distension in healthy humans (4, 43).Serotonergic (5-HT) mechanisms also alter gut absorptive, motor, and sensory functions via actions in the gut, spinal cord, and brain stem (27). Ligand-receptor interaction results in c...

Alpha-2-adrenergic receptor gene polymorphism in Turkish population with irritable bowel syndrome

“…Our data showed that C-1291G polymorphism in ADRA2A was not different in the patient and control groups, so there was no significant association between ADRA2A C-1291G polymorphism and IBS in Turkish population. Our results were similar to those of Camilleri, that he could not detect any relation between α2A genotype and subtypes of IBS (14). The high number of C-IBS and very low number of D-IBS patients might be the reason for statistical nonsignificance since ADRA2A is found to be responsible for mediating intestinal antisecretory action and probably is involved in pathogenesis of D-IBS (15)(16)(17)(18)(19).…”

Epidemiology of Functional Gastrointestinal Disorders in Japan and in the World

“…82 5-HTTLPR LS/SS genotype is also associated with both increased pain sensation and increased rectal compliance. 83 Serotonin is produced in the GI tract, brain, and neuronal cells, and is involved in GI motility and sensation. SERT regulates the amount of serotonin, and the S/S allele is associated with lower expression of SERT than the L/L allele, with serotonin absorption being half that of the L/L allele.…”

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

“…The 5-HTTLPR genotype (S allele) is associated with higher pain sensory ratings during rectal distension studies in health and IBS, and the increased sensation ratings in carriers of the S allele are not caused by lower rectal compliance (19).…”