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

Abstract

The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, ␣ 2-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNF␣, GN␤3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT3 genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klotho␤ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published. adrenergic; serotonergic; solute carrier 6A4; 5-hydroxytryptamine transporter-linked polymorphic region; inflammation; susceptibility; klotho␤; bile acid malabsorption EPIDEMIOLOGICAL STUDIES of familial aggregation (57, 99) and twins (7,70,72,82,83) suggest a genetic contribution to irritable bowel syndrome (IBS). While the data are conflicting, they are generally consistent with the hypothesis that IBS may be a complex genetic disorder. Understanding of genetic variation and its influence on gut motility, secretion, sensation, and inflammation, as it is applied to IBS, has the potential to help elucidate mechanisms of control of a poorly understood syndrome. Similarly, the impact of genetic variation on the targets of therapy in IBS may enhance the efficacy of pharmacological therapies. These targets include receptors and regulators of gut function and variations in drug metabolism.This review addresses the available literature on the role of genetics in IBS. There are no published genome-wide association studies in functional gastrointestinal (GI) or motility disorders specifically focusing on genetic epidemiology and pharmacogenetics. Genetic Epidemiology of IBS: Candidate Gene ApproachAs the general approach followed in genotype association studies (Fig. 1), investigators have sought the relationship between genotype and clinical phenotype, while appreciating that intermediaries, such as th...

Association Between SLC6A4 Serotonin Transporter Gene Lainked Polymorphic Region and ADRA2A −1291C>G and Irritable Bowel Syndrome in Korea

“…Discrepancy in genotype distribution of SLC6A4 5-HTTLPR between Caucasian and Asian patients was well documented. 17,18,48 Nonetheless, the genotypic distributions of most polymorphisms in controls of this study were similar to those of other studies conducted in Korea, Japan and China lending strength to the validity of our result particularly in Asian countries. 13 We also have to admit the small sample size of overall patients, especially IBS-C in this study may have limited its accuracy to detect differences between the groups.…”

“…The facts that most of serotonin is synthesized in the intestine and the presence of many kinds of receptors within the intestinal wall involving gastrointestinal secretion, motility, and visceral perception implies that serotonin or serotonin signaling pathway may contribute to IBS. 17 In particular, SERT play an important role in modulating the level of serotonin, 26 and excessive transcription of SERT in those with L allele would show high reuptake activity of serotonin and subsequently, reducing it in the synaptic cleft. 27 There are studies similar with our result about SERT polymorphism.…”

“…[11][12][13][14][15] The genetic variation in the adrenergic receptor such as ADRA2A −1291C>G has been proposed as a mechanism for the modification of motor and sensory functions in IBS patients. 16,17 Another protein of interest is the G-protein. Common GNB3-825C>T polymorphism has been believed to be associated with enhanced G-protein activation, 18 and there are several studies which indicate a significant association with functional dyspepsia.…”

Irritable Bowel Syndrome : Studies of central pathophysiological mechanisms and effects of treatment

“…In recent years, however, other mechanisms have been proposed, such as low-grade inflammation, increased intestinal mucosal permeability, immunologic and genetic factors, altered intestinal microbiota, and dietary factors. [14][15][16][17] These theories indicate the heterogeneity of pathophysiological mechanisms in the IBS population. 17 In addition, the importance of psychological and social factors such as social learning, comorbid psychiatric disorders, chronic life stress, and impaired coping is evident in IBS.…”

Polymorphisms: genetic variations associated with irritable bowel syndrome

“…Thus, to date, over 50 genes with a specific role in the motor, secretory, and intestinal barrier functions, in the immune function, and in psychiatric disorders have been evaluated (4,5). One the best researched areas in IBS is the immune function, given the differences identified in these patients versus the healthy population, the presence of low-grade mucosal microinflammation, and the latter's association with intestinal dysfunction in these patients (6,7). Furthermore, several immune mediators in the plasma have been posited as biomarkers for the diagnosis of IBS because of their differential expression from control subjects.…”