Genetics and irritable bowel syndrome: from genomics to intermediate phenotype and pharmacogenetics

Abstract

Purpose: Familial aggregation and sibling pair studies suggest there is a genetic contribution to the development of irritable bowel syndrome (IBS). The aim of this study was to review the evidence of genetics in IBS based on genetic epidemiology, studies of association with intermediate phenotypes and pharmacogenetics.

Results: Genetic association studies with IBS symptom phenotype have generally provided inconsistent results for many candidate genes investigated, such as SLC6A4, GNB3, and IL-10. There have been no genome-wide association studies in IBS to date. Studies of associations of candidate genes with intermediate phenotypes suggest associations with pathophysiological mechanisms of motor and sensory functions; however, these results also require replication. Pharmacogenetics studies illustrate the potential of genetics to impact on response to therapy, as observed with SLC6A4 and responses to the 5-HT3 antagonist alosetron and the 5-HT4 agonist, tegaserod.

Conclusions: While the heritable component and genetics in the complex disorder of IBS are still poorly understood, studies of the associations of spontaneous genetic variations and altered functions may provide novel insights of the mechanisms contributing to the disease.

Figure 1

Upper panel: In genotype association studies, the relationship between genotype and clinical phenotype includes “black box” intermediaries such as the effect of the environment and other unknown biological factors. Identification of significant association therefore requires large numbers of participants. Lower panel: In genotype-endophenotype association studies, the relationship between candidate genes that affect the biomarkers (endophenotype) of interest is explored with confidence that the biomarkers are associated with a known (often robust) relationship with the main manifestations of the clinical phenotype. Since the biomarker functions are measurable and have a defined coefficient of variation, the size of the function that is detectable can be used to inform the much smaller sample size for the genetic association study.

Figure 2

Summary of genetic associations that have been explored to date in patients with functional gastrointestinal disorders, predominantly IBS, provide a model of the candidate mechanisms involved in the motor and sensory disorders associated with IBS. Thus, NPSR1 may enhance barrier permeability, 5-HTTLPR alter the reuptake of 5-HT released from enteroendocrine cells in response to chemical or mechanical stimuli in the lumen, adrenergic receptors alter sympathetic input, and cannabinoid mechanisms (through changes in the function of the rate-limiting enzyme for anandamide, fatty acid amide hydrolase, FAAH) alter cholinergic supply to the smooth muscle cell. Moreover, the function of the myocyte is influenced by energy generation that depends on mitochondrial DNA.