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

Michael Camilleri, David A. Katzka
2012 American Journal of Physiology - Gastrointestinal and Liver Physiology  
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
more » ... ond 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 Approach As 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 the effect of the environment and other unknown biological factors, are largely unexplored. With this degree of imprecise control or knowledge of potential contributing factors, the identification of significant associations requires large numbers of participants and, importantly, replication of findings in different cohorts or ethnic groups. A second approach explores genotype-endophenotype association studies, that is, the relationship between candidate genes and quantitative traits (biomarkers, intermediate phenotypes, or endophenotypes) of interest. Endophenotypes are defined here as phenotypes that bear a closer relationship to the biological processes that give rise to the illness, have a hereditary component and cosegregate with illness within families, and are independent of whether or not the illness is active (46). Such biomarkers or quantitative traits typically are measurable, have a defined coefficient of variation, usually have a known relationship with the main manifestations of the clinical phenotype, and provide opportunities to assess genetic associations with much smaller sample sizes. By studying the genetic associations between candidate genes and intermediate phenotypes that are associated with manifestations of the clinical phenotype, one can also evaluate the role of the candidate mechanism in IBS (see Fig. 1 adapted from Ref. 53). The intermediate phenotypes most commonly used in IBS are colonic transit, colonic motility and compliance, and sensation thresholds and ratings. Details regarding the published gene polymorphisms associated with IBS, the magnitude and significance of the disease association, the sample size, and the replication of findings are summarized in an extensive review by Saito et al. (97). Neurotransmitter Mechanisms Serotonin. Serotonin [5-hydroxytryptamine (5-HT)] is involved in controlling GI secretion, motility, and visceral perception (41, 63). It is, therefore, not surprising that, in patients with IBS, studies have documented alterations in 5-HT levels (6) and 5-HT signaling (4); serotonin and serotonin receptormodulating drugs are vigorously pursued in IBS, despite poor consensus on the optimal end points for trials and the regulatory agency requirement of rigorous safety standards for serotonergic agents because of potential vascular effects (14, 15, 24). As a result of the widespread interest in serotonin, genetic Address for reprint requests and other correspondence: M. Camilleri, Mayo Clinic, Charlton 8-110, 200 First St. SW, Rochester, MN 55905
doi:10.1152/ajpgi.00537.2011 pmid:22403795 pmcid:PMC3362100 fatcat:kfztaqlmavh5vaqtkf7k5ehi3e