Genetic polymorphisms of SCN10A are associated with functional dyspepsia in Japanese subjects

Arisawa, Tomiyasu; Tahara, Tomomitsu; Shiroeda, Hisakazu; Minato, Takahiro; Matsue, Yasuhiro; Saito, Takashi; Fukuyama, Tomoki; Otsuka, Toshimi; Fukumura, Atsushi; Nakamura, Masakatsu; Shibata, Tomoyuki

doi:10.1007/s00535-012-0602-3

Cited by 28 publications

(20 citation statements)

References 31 publications

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“…5C) sodium currents density was greatly enhanced in NMD rats compared with controls. This is in agreement with previous reports that TTX-R sodium current is involved in somatic pain (21) and visceral pain (2,22). Possible mechanisms for the potentiation of TTX-R sodium currents include an increase in single-channel conductance, channel opening probability, and/or upregulation of Na V 1.8 or/and Na V 1.9 expression.…”

Section: Discussionsupporting

confidence: 93%

Neonatal maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats

Xiao

Zhu

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats. Am J Physiol Gastrointest Liver Physiol 304: G311-G321, 2013. First published November 8, 2012; doi:10.1152/ajpgi.00338.2012.-Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by abdominal pain in association with altered bowel movements. The underlying mechanisms of visceral hypersensitivity remain elusive. This study was designed to examine the role for sodium channels in a rat model of chronic visceral hyperalgesia induced by neonatal maternal deprivation (NMD). Abdominal withdrawal reflex (AWR) scores were performed on adult male rats. Colon-specific dorsal root ganglion (DRG) neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel current under whole-cell patch-clamp configurations. The expression of NaV1.8 was analyzed by Western blot and quantitative real-time PCR. NMD significantly increased AWR scores, which lasted for ϳ6 wk in an association with hyperexcitability of colon DRG neurons. TTXresistant but not TTX-sensitive sodium current density was greatly enhanced in colon DRG neurons in NMD rats. Compared with controls, activation curves showed a leftward shift in NMD rats whereas inactivation curves did not differ significantly. NMD markedly accelerated the activation time of peak current amplitude without any changes in inactivation time. Furthermore, NMD remarkably enhanced expression of Na V1.8 at protein levels but not at mRNA levels in colon-related DRGs. The expression of NaV1.9 was not altered after NMD. These data suggest that NMD enhances TTXresistant sodium activity of colon DRG neurons, which is most likely mediated by a leftward shift of activation curve and by enhanced expression of NaV1.8 at protein levels, thus identifying a specific molecular mechanism underlying chronic visceral pain and sensitization in patients with IBS. dorsal root ganglion; neonatal maternal deprivation; irritable bowel syndrome; visceral pain; voltage-gated sodium channel IRRITABLE BOWEL SYNDROME (IBS) remains a common and challenging disorder for clinicians. It is defined by recurrent symptoms of abdominal pain or discomfort associated with alterations in bowel habits. The pathophysiology of IBS involves psychological disorder, altered intestinal motility, and visceral hypersensitivity (18, 33). However, the exact causes of IBS have not been clearly elucidated and effective therapeutics for the primary symptoms has been unavailable. Psychological factors and stresses appear to play an important role in the development of IBS (4, 39). Recent studies in rodents found that early life stress in the form of neonatal maternal deprivation (NMD) induced rats to develop stress-produced intestinal mucosal dysfunction and visceral hypersensitivity at adulthood, mimicking main pathophysiological features of IBS in human (3,12,20). Indeed, early traumatic experiences such as childhood neglect, abuse, loss of a parent, and lif...

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Section: Discussionsupporting

confidence: 93%

Neonatal maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats

Xiao

Zhu

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In all FD, the CC genotype of TRPV1G315C polymorphism, and the gene polymorphisms of the tetrodotoxin resistant sodium channel NaV1.8, encoded by SCN10A were the only positive polymorphisms preventing the development of FD. 92,93 These data indicate that genetic factors are involved in the development of FGIDs. However, the odds ratio that can be acquired by these polymorphisms is maximally two to three.…”

Section: Genetics and Early Life Eventsmentioning

confidence: 82%

Epidemiology of Functional Gastrointestinal Disorders in Japan and in the World

Oshima

Miwa

2015

J Neurogastroenterol Motil

140

130

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Functional gastrointestinal disorders (FGIDs), represented by functional dyspepsia (FD) and irritable bowel syndrome (IBS), are a group of disorders that include variable combinations of chronic or recurrent gastrointestinal symptoms not explained by structural or biochemical abnormalities. FGIDs account for a significant percentage of patients seen in primary care settings with abdominal symptoms. Although the definition of FGIDs can easily affect the prevalence, the prevalences of dyspepsia/FD and IBS diagnosed by the Rome III criteria in the general population are 5.3-20.4% and 1.1-29.2%, respectively. Recent reports of FD and IBS defined by the Rome III criteria indicated a female predominance. Regarding the subtype prevalence of FD, postprandial distress syndrome was more prevalent than epigastric pain syndrome (5.6-13.9% vs 0.9-9.5%). The subtype prevalence of IBS is characterized by male predominance for IBS with diarrhea and female predominance for IBS with constipation. Factors affecting the development of FGIDs such as epidemiological factors including genetic and environmental factors, are important. Gene polymorphisms are involved in the development of FGIDs. The prevalence differs among races and geographic areas. Foods may affect the development of FGIDs, but the causal relationships between food and FGIDs are not conclusive. The symptoms often regress and appear in the course of these entities. Building a favorable patient-doctor relationship is effective for controlling symptoms of FGIDs. Physicians should explain that FGIDs are highly prevalent conditions, impair the patients' quality of life even without evident underlying organic causes and are not life-threatening conditions to ensure patients' understanding.

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“…There are reports of associations between functional dyspepsia and gene polymorphisms including G-protein beta3 [49] and SCN10A [50] but these data need confirmation. Also how genetic factors may influence the clinical manifestation of FD patients needs to be determined.…”

Section: Geneticsmentioning

confidence: 97%

Women and Functional Dyspepsia

Napthali

Koloski

Walker

et al. 2016

Womens Health (Lond Engl)

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Functional dyspepsia is relatively common yet poorly understood. The best accepted diagnostic criteria are the Rome III criteria. The epidemiology, healthcare seeking rates, impact and pathophysiology are reviewed with a focus on women. Treatment is limited with no clearly established regimen currently recommended. Duodenal eosinophilia may be found in a subset. Proton pump inhibitors and prokinetic agents represent the standard therapeutic regimen after Helicobacter pylori infection has been eliminated. Some novel agents such as the prokinetic acotiamide appear promising; however, the need for a safe and efficacious treatment remains largely unmet. This review also describes the currently available management options for functional dyspepsia.

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Genetic polymorphisms of SCN10A are associated with functional dyspepsia in Japanese subjects

Abstract: We conclude that genetic polymorphisms of SCN10A are closely associated with FD (both EPS and PDS), especially in H. pylori-negative subjects, in Japanese.

Cited by 28 publications

References 31 publications

Neonatal maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats

Neonatal maternal deprivation sensitizes voltage-gated sodium channel currents in colon-specific dorsal root ganglion neurons in rats

Epidemiology of Functional Gastrointestinal Disorders in Japan and in the World

Women and Functional Dyspepsia

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