Evidence for Genotypic Influences

Anecdotally, FGD appear to cluster in families, and recent research has confirmed these impressions. A large questionnaire-based same-sex twin pair study in Australia suggested a substantial proportion of the liability for FGD was under genetic control with a calculated heritability of 57%, and the remaining 43% being attributed to the individual's unique environment (133). A much larger questionnaire-based study by Levy et al. found a greater concordance for IBS in monozygotic versus dizygotic twins (17.2% vs. 8.4%, p = 0.03), supporting a genetic contribution to IBS (134); however, logistic regression analysis suggested that having a mother or father with IBS were independent predictors of IBS status (p < 0.001) and stronger predictors than having a twin with IBS. Therefore, although heredity certainly contributes to the development of IBS, social learning has an equal or greater influence.

Serotonin (5-HT) plays an important role in gut function and sensory signalling in the brain-gut axis. It is not only an important neurotransmitter in the enteric nervous system, stimulating both vagal and intrinsic (enteric) afferent fibers, but is also a signalling molecule participating in mucosal sensory transduction (135). Ninety-five percent of the 5-HT in the body is found in the GI tract where it is contained in enterochromaffin cells in the epithelial lining of the gut (90%) and in enteric neurons of the submucosal and myenteric plexuses (10%). The remaining 5% is found in the brain. There are seven subtypes of 5-HT receptors differentiated on the basis of structure and function (135). As a result of these features, it plays a pivotal role in initiating a wide range of intestinal responses and reflexes. The reuptake of 5-HT provides an adequate means of terminating its effects after it has exerted its synaptic action, and is mediated by the 5-HT transporter SERT. Deletion polymorphisms in SERT, producing short allelic variants, have been linked with diarrhea predominant IBS in women (136), and anxiety-related personality characteristics (137). Females homozygous for these short allelic variants have also been shown to demonstrate elevated behaviorally evoked heart rate reactivity (138). It is possible that these polymorphisms that reduce the efficacy of SERTas a transporter allow ongoing 5-HT-mediated effects at the synaptic junction, resulting in clinical consequences.

As mentioned earlier, sympathetic adrenergic dysfunction has been demonstrated in a subgroup of patients with IBS (122). Bharucha et al. compared the effects of saline (control) against clonidine (a2-agonist), yohimbine (a2-antagonist), phenylephrine (a1-agonist), and rito-drine (P2-agonist) on colonic motility, compliance, and sensation in healthy human volunteers (139). They demonstrated that clonidine reduced fasting colonic tone and phasic activity, increased colonic compliance, and markedly attenuated the perception of pain during colo-nic balloon distension, whereas yohimbine increased fasting colonic tone and enhanced colonic perception of pain. The other drugs tested showed no effects at the doses used which were said to be the maximal permissible in humans. These findings suggest a role for the a2-adrenoceptor in modulating colonic motor and sensory function in the human GI tract.

Three human a2-adrenoceptor subtypes have been identified: a2A, a2B, and a2C (140). Prejunctional a2A and a2C adrenoceptor subtypes regulate the release of NE from sympathetic nerves through negative feedback at presynaptic nerve endings. Synaptic content of NE is modified by the NE transporter. Mutations in the NE transporter that reduce its efficacy in removing NE from the synapse could prolong the effects of NE, thereby resulting in a functional overstimulation of the sympathetic nervous system in response to physiological stimuli, possibly resulting in increased gut motility or enhanced sensory signalling. Recently, both SERT and a2-adrenoceptor polymorphisms have been associated with high somatic symptom scores in FGD (141). As mentioned, anxiety and visceral hypersensitivity are both associated with FGD; however, whether these polymorphisms predict pain sensitivity to an adverse stimulus (such as esophageal acidification) is unknown.

Apart from abnormalities in reuptake transporters as described above, a role for underlying second messenger abnormalities has also been proposed. Holtmann et al. reported the association of functional dyspepsia with specific G-protein P3 subunit genotypes (142). G-pro-teins are heterotrimeric second messenger proteins that are essential in mediating cellular responses by coupling extracellular receptor activation to intracellular effector systems such as adenylcyclases and protein kinases (143). Approximately 80% of all known membrane receptors transduce their signals via heterotrimeric G-proteins. G-proteins are composed of different a, P, and y subunit isoforms, the P-y subunit forming a functional monomer. On receptor activation, both a and P-y subunits dissociate from the receptor to then modulate a variety of intracellular effector systems. Dysfunction of these important second messenger systems could therefore alter intracellular signal transduction (142). A common C825T polymorphism has been described in the gene GNB3 that encodes the P3 subunit of heterotrimeric G-proteins, which gives rise to 3 possible genotypes—CC, TC, or TT. The 825T allele of the TC or TT genotype is associated with alternative splicing of the gene and the formation of a truncated but functionally active splice variant (142). The 825T allele is associated with enhanced G-protein activation and increased cellular responses, and to that effect has been linked with enhanced a2-adrenoceptor-mediated coronary vasoconstriction in GNB3 825T allele carriers (144). Individuals who are homozygous 825C allele carriers (CC genotype) form much reduced quantities of the P3 splice variant and demonstrate reduced signal transduction responses. The GNB3 subunit has been proposed as a susceptibility factor for depression, and may predict the response to treatment with antidepressants (145). In addition, in vitro cellular studies have demonstrated the C825T allele to be associated with enhanced lymphocyte proliferation and chemotaxis (146).

Do Not Panic

Do Not Panic

This guide Don't Panic has tips and additional information on what you should do when you are experiencing an anxiety or panic attack. With so much going on in the world today with taking care of your family, working full time, dealing with office politics and other things, you could experience a serious meltdown. All of these things could at one point cause you to stress out and snap.

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