Irritable bowel syndrome (IBS) is a common disorder that has been shown to aggregate in families and to affect multiple generations, but not in a manner consistent with a major Mendelian effect. Relatives of an individual with IBS are 2 to 3 times as likely to have IBS, with both genders being affected. To date, more than 100 genetic variants in more than 60 genes from various pathways have been studied in a number of candidate gene studies, with several positive associations reported. These findings suggest that there may be distinct, as well as shared, molecular underpinnings for IBS and its subtypes.
As discussed in articles elsewhere in this issue, irritable bowel syndrome (IBS) is a chronic disorder characterized by abdominal pain or discomfort and diarrhea and/or constipation that can be associated with altered gastrointestinal motility and visceral sensation. The chronicity of IBS symptoms and the lack of a cure or effective treatments result in loss of work and school productivity and impaired personal and health-related quality of life. Patients, their relatives, and friends frequently ask difficult questions, such as why they in particular developed IBS. Although diet, psychological factors, infection, and gut flora may attenuate IBS symptoms, there is no simple answer to this question. As other family members may concurrently have bowel disturbances, the role of genes in disease development—and the sense of personal destiny it invokes—is somewhat intuitive, easy to accept, but also difficult to refute with facts or objective findings arguing the contrary.
Great advances have been made in genetics in recent years. As the efficiency, ease, and cost of genotyping has decreased, our understanding of DNA sequence, structure, and function has improved dramatically. Previously, laboratory-based study of the human genome was often restricted to known genes and coding exon regions and study of a handful of genetic variants. Now, high-throughput technology allows genotyping of thousands to a million genetic markers across the genome, and sequencing of nearly the entire [coding] human genome is now possible. Furthermore, advances in data storage and analysis of these large quantities of data has led to the discovery of susceptibility loci for several diseases including, notably, Crohn’s disease. These amazing scientific strides have led many to believe that “virtually every human ailment, except perhaps trauma, has some basis in our genes.” ( www.genome.gov ). This premise has appealed to many IBS researchers, and several have commenced in trying to identify an IBS gene or set of genes.
Despite the acceptance by some that genes may cause—or at least contribute to the development of—IBS, careful examination of the body of literature is necessary to determine whether there is sound basis for this theory, as gene discovery still requires considerable time, effort and, thus, financial resources. Alternative hypotheses, such as environmental exposures, certainly exist and cannot be ignored as important players in IBS. This article provides a summary of the studies around the competing hypotheses of “gene versus environment” or “nature versus nurture” in IBS. An overview of family studies, candidate gene studies, and alternative hypotheses for IBS are covered, to provide the reader an overview of the works conducted in this area.
IBS as a complex genetic disorder
Classic Mendelian genetics diseases are typically caused by a few highly penetrant genetic defects on a single gene and are transmitted in a typical pattern through families. Mendelian diseases follow an autosomal dominant, recessive, codominant, or X-linked pattern of transmission through pedigrees. Recent genetic studies have focused less on Mendelian disorders and more on complex genetic diseases. A “complex genetic disease” is defined as a multifactorial genetic disorder resulting from multiple genetic variants on several genes (ie, polygenic) with contributions from environment and lifestyle. These genetic effects are modest in that the presence of a specific variant is rarely sufficient on its own to result in disease development. Complex genetic diseases are still heritable in that they tend to aggregate in families, but not in the same predictable fashion as classic Mendelian disorders.
Many common diseases of significant public health interest are thought to be complex disorders. Heart disease, hypertension, diabetes, obesity, autism, and mood disorders are a few of the diseases and disorders under study by geneticists and genetic epidemiologists. In gastroenterology, Crohn’s disease is the best example of a complex genetic disorder with successful susceptibility loci identification. A combination of family-based linkage studies, candidate gene and fine-mapping studies, as well as genome-wide association studies have led to the identification of several genes—such as NOD2 , ATG16L1 , IL23 , IL12B , STAT3 , NKX2-3 —found to be consistently associated with Crohn’s disease. These discoveries offer the promise that if gene discovery was possible in this complex gastrointestinal disorder, successful gene discovery is feasible in other multifactorial disorders and diseases including IBS.
Despite the discovery of several genetic loci involved in the development of Crohn’s disease, it is clear that genes alone do not cause the disease and that environmental contributions, such as diet, smoking, early exposure to infectious organisms, and colonic microflora, are still important. A similar gene-environment paradigm could be proposed for IBS ( Fig. 1 ) whereby a combination of genetic factors and environmental factors result in the alterations in gastrointestinal sensation and motor function that ultimately result in manifestation of symptoms. Genetic variation in genes that encode proteins that regulate gender-based biologic processes, control or modulate central or peripheral sensation and motility, or even regulate brain response to stress would be the obvious first candidates for IBS. These factors, interacting with environmental factors such as diet, infection, and early life trauma and stress, are likely responsible for the overall IBS phenotype. However, the specific combinations of genetic variants and environmental factors likely can in part explain the clinical heterogeneity of IBS. Hence, it is conceivable and likely that genes responsible for diarrhea are different to those responsible for constipation, and other genetic variants that predispose an individual to developing or sensing abdominal pain required for IBS are not generally present in the nonpainful functional disorders such as functional constipation and functional diarrhea. Exploring gene-environment interactions will be important if one postulates that IBS is a multifactorial, polygenic complex genetic disorder.
Related posts:
Inflammation and Microflora
Therapies Aimed at the Gut Microbiota and Inflammation: Antibiotics, Prebiotics, Probiotics, Synbiotics, Anti-inflammatory Therapies
Centrally Acting Therapies for Irritable Bowel Syndrome
Inflammation and Microflora
The Role of Diagnostic Testing in Irritable Bowel Syndrome
Emerging Pharmacological Therapies for the Irritable Bowel Syndrome
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