The Genetics of Irritable Bowel Syndrome

Saito, Yuri; Petersen, Gloria M.; Locke, G. Richard; Talley, Nicholas J.

doi:10.1016/s1542-3565(05)00184-9

Cited by 85 publications

(54 citation statements)

References 55 publications

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“…Whilst several candidate genes have been proposed, no study to date has identified an "IBS" gene, although it must be noted that several of the published studies are small and statistically under powered to detect what is probably a small influence (see the review by Saito and Talley 65 ). Large population based, genome wide association studies represent one of the most exciting potential avenues for delineating the genetic factors that contribute to the development of FGID in the future but the prerequisite step is the further definition of the clinical phenotype based on pathophysiological features rather than purely symptom based criteria.…”

Section: Psychological and Genetic Influencesmentioning

confidence: 99%

Gut pain & visceral hypersensitivity

Farmer

Aziz

2013

British Journal of Pain

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Visceral pain is a highly complex entity whose experience is variable in health and disease. It can occur in patients with organic disease and also in those without any readily identifiable structural or biochemical abnormality such as in the functional gastrointestinal disorders (FGID). Despite considerable progress in our understanding of the culpable underlying mechanisms significant knowledge gaps remain, representing a significant unmet need in gastroenterology. A key, but not universal, pathological feature is that patients with FGID often display heightened sensitivity to experimental gut stimulation, termed visceral hypersensitivity. A plethora of factors have been proposed to account for this epiphenomenon including peripheral sensitization, central sensitization, aberrant central processing, genetic, psychological and abnormalities within the stress responsive systems. Further research is needed, bringing together complementary research themes from a diverse array of academic disciplines ranging from gastroenterology to nociceptive physiology to functional neuro-imaging, to address this unmet need.

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Section: Psychological and Genetic Influencesmentioning

confidence: 99%

Gut pain & visceral hypersensitivity

Farmer

Aziz

2013

British Journal of Pain

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“…SERT develops before fetal expression of TPH1 or TPH2 is evident, and thus, for mucosal SERT expression to be influenced by serotonin, the source of the serotonin would have to be maternal. IBS does appear to have a familial contribution, although twin studies have shown only a modest contribution of genetics (34). It is thus possible that maternal serotonin can contribute to fetal bowel development and account for a familial transmission that is independent of the genetic makeup of the fetus.…”

Section: Maternal Serotonin May Be a Morphogen-like Signaling Moleculementioning

confidence: 99%

Maternal serotonin is crucial for murine embryonic development

Côté

Fligny

Bayard

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

334

198

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The early appearance of serotonin and its receptors during prenatal development, together with the many effects serotonin exerts during CNS morphogenesis, strongly suggest that serotonin influences the development and maturation of the mammalian brain before it becomes a neuromodulator/neurotransmitter. Sites of early serotonin biosynthesis, however, have not been detected in mouse embryos or extraembryonic structures, suggesting that the main source of serotonin could be of maternal origin. This hypothesis was tested by using knockout mice lacking the tph1 gene, which is responsible for the synthesis of peripheral serotonin. Genetic crosses were performed to compare the phenotype of pups born from homozygous and heterozygous mothers. Observations provide the first clear evidence that (i) maternal serotonin is involved in the control of morphogenesis during developmental stages that precede the appearance of serotonergic neurons and (ii) serotonin is critical for normal murine development. Most strikingly, the phenotype of tph1؊/؊ embryos depends more on the maternal genotype than on that of the concepti. Consideration of the maternal genotype may thus help to clarify the influence of other genes in complex diseases, such as mental illness.genotype/phenotype ͉ tph1 knockout mice ͉ tryptophan hydroxylase S erotonin participates in a wide range of physiological systems including the control of gastrointestinal motility and secretion, cardiovascular regulation, hemostatic processes, the regulation of circadian rhythms, the sleep-wake cycle, perception of pain, appetite, manifestation of nausea, and sexual behavior. Accumulating in vitro evidence also indicates that serotonin signaling participates in the regulation of development in many animal phyla before the onset of neurogenesis. Serotonin thus plays a role in development before it acts as a neurotransmitter (1-3). Serotonin affects craniofacial, gastrointestinal, and cardiovascular morphogenesis in chicken, rat, and mouse; these effects are often mediated by the serotonin 2B receptor (4-7). Altogether, the presence of serotonin, its receptors, and transporter during development and the ability of compounds that modulate serotonergic signaling to interfere with development suggest that serotonin functions as a humoral morphogen (8-10). Sites of early serotonin biosynthesis, however, have not been detected in embryos or extraembryonic structures of the mouse. It has therefore been assumed that the main source of serotonin is maternal (11).We have generated a mouse line deficient in peripheral serotonin biosynthesis. Targeted disruption of the tryptophan hydroxylase 1 (tph1) gene resulted in levels of circulating serotonin that are only 3-15% of those of normal mice. The null mutants (tph1Ϫ/Ϫ) from heterozygous crosses are viable and display no gross anatomical abnormalities, but they develop cardiac insufficiency in adulthood (12). The tph1Ϫ/Ϫ mice thus provide a convenient tool to address the developmental role of maternal serotonin. tph1-null females were bred...

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“…One of the most common forms of visceral pain and abdominal discomfort is irritable bowel syndrome (IBS). Several studies have concluded that there is strong genetic component in the incidence of IBS (familial IBS), and many candidate genes have been investigated, although no strong association with any of the candidate genes, such as P2X3 or TRPV1, has been found (66). The observation that families with SCN5A-related cardiac channelopathies report much higher incidence of abdominal pain than a control population has led to the hypothesis that sodium channelopathies may be a contributing cause in the pathogenesis of functional bowel disorders (67).…”

Section: Visceral Painmentioning

confidence: 99%

Pain as a channelopathy

Raouf¹,

Quick

Wood

2010

J. Clin. Invest.

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Mendelian heritable pain disorders have provided insights into human pain mechanisms and suggested new analgesic drug targets. Interestingly, many of the heritable monogenic pain disorders have been mapped to mutations in genes encoding ion channels. Studies in transgenic mice have also implicated many ion channels in damage sensing and pain modulation. It seems likely that aberrant peripheral or central ion channel activity underlies or initiates many pathological pain conditions. Understanding the mechanistic basis of ion channel malfunction in terms of trafficking, localization, biophysics, and consequences for neurotransmission is a potential route to new pain therapies.

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The Genetics of Irritable Bowel Syndrome

Cited by 85 publications

References 55 publications

Gut pain & visceral hypersensitivity

Gut pain & visceral hypersensitivity

Maternal serotonin is crucial for murine embryonic development

Pain as a channelopathy

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