The HTR3A Polymorphism c. -42C>T Is Associated With Amygdala Responsiveness in Patients With Irritable Bowel Syndrome

Abstract

Background & Aims 5-HT3 receptor (5-HT3R) antagonists are effective in treating patients with irritable bowel syndrome (IBS) and have anxiolytic effects. Their therapeutic effects are related, in part, to reducing amygdala engagement during expected visceral pain. A single nucleotide polymorphism (SNP) in HTR3A, c.-42C>T;(C178T; rs1062613), is associated with altered reactivity of the amygdala during emotional face processing in healthy subjects (controls). We evaluated the influence of this SNP on amygdala reactivity to emotional faces and non-emotional stimuli in female patients with IBS and controls. Methods We measured brain responses during an affect-matching paradigm in 54 women (26 with IBS, 29 controls) using functional magnetic resonance imaging. We examined associations between HTR3A c.-42C>T genotype (C/C vs. T carrier) and responses in amygdala and other regions of brain that expressed high levels of 5-HT3R. Results The C/C genotype was associated with greater anxiety symptoms in patients with IBS and controls and increased activation of the amygdala under emotional and non-emotional conditions. Among patients with IBS, the C/C genotype was associated with greater symptom ratings; a subset of IBS patients with the C/C genotype had increased amygdala responses to non-emotional stimuli, compared to other subjects with C/C genotype. Conclusions Regardless of diagnosis, the C/C genotype of the c.-42C>T polymorphism in HTR3A, compared to T carrier status, is associated with increased anxiety and amygdala responsiveness during emotional and non-emotional tasks. This polymorphism was associated with severity of IBS symptoms. Although this genotype is not sufficient for diagnosis of IBS, it is associated with severity of symptoms.

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…[53,54] In some studies at least, sex and genetic differences have been identified in IBS-induced amygdala hyperactivity, and stronger effects are observed in males [55] and those with a particular polymorphism of the serotonin receptor gene, HTR3A. [56] Overall, amygdala hyperactivity seems to be related to chronic visceral hypersensitivity, pointing to another important link between the gut and the amygdala.…”

Epidemiology of Functional Gastrointestinal Disorders in Japan and in the World

“…80 The C/C genotype of the -42C>T polymorphism in HTR3A, compared with T carrier status, is associated with the severity of IBS symptoms. 81 The gene polymorphism of 5-HTTLPR is related to the development of IBS-D in females. 82 5-HTTLPR LS/SS genotype is also associated with both increased pain sensation and increased rectal compliance.…”

Evidence-based clinical practice guidelines for irritable bowel syndrome

“…However, IBS has not been definitively linked to a particular gene [34], despite previous reports of IBS candidate genes such as a 2 A (C-1291G), a 2 C (Del 332-325) and GNb3 (C825T). However, there have been recent reports of the association between serotonin transporter gene polymorphism and visceral hypersensitivity [34], between serotonin transporter gene polymorphism and the activation of the anterior cingulate cortex at the time of visceral stimulation [35], and between 5-HT 3 A receptor gene polymorphism and the activation of the amygdala at the time of visceral stimulation [36], which all point to the association of IBS and endophenotypes. In a cohort study of patients with a history of infectious enteritis, two of the four genes that were linked to IBS were toll-like receptor 9 (TLR9) genes that play a role in self/nonself pattern recognition in the innate immune system [37].…”