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

doi:10.1053/j.gastro.2011.03.011

Gastroenterology

Volume 140, Issue 7, June 2011, Pages 1943-1951

https://doi.org/10.1053/j.gastro.2011.03.011 Get rights and content

Background & Aims

5-Hydroxytryptamine (5-HT)3 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 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 single nucleotide polymorphism on amygdala reactivity to emotional faces and nonemotional 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 nonemotional conditions. Among patients with IBS, C/C genotype was associated with greater symptom ratings. A subset of IBS patients with the C/C genotype had increased amygdala responses to nonemotional stimuli, compared with other subjects with C/C genotype.

Conclusions

Regardless of diagnosis, the C/C genotype of the c.-42C>T polymorphism in HTR3A, compared with T carrier status, is associated with increased anxiety and amygdala responsiveness during emotional and nonemotional 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.

Section snippets

Subjects

A sample of 26 female IBS patients and 29 female healthy controls (demographics are presented in Table 1) participated in functional magnetic resonance image (fMRI) studies of emotional reactivity and provided saliva samples for DNA analyses. Subjects were recruited through the University of California Los Angeles Digestive Disease Clinic and from community advertisements. The diagnosis of IBS was confirmed using Rome II criteria during a clinical examination by a gastroenterologist or nurse

HTR3A polymorphism

Fifteen of 29 HCs and 16 of 26 IBS patients were homozygous for the C allele, 9 HCs and 7 patients carried the heterozygous C/T genotype, and 5 HCs and 3 patients carried the homozygous T/T genotype. The c.-42C>T SNP had been found previously to be associated with IBS-D in a UK sample applying a minor allele dominant model.²⁴ Thus, subjects carrying a T allele (C/T or T/T) were combined into a single group (T carriers) for analyses.

A HTR3A genotype (C/C, T carrier) × diagnosis (HC, IBS)

Discussion

We used a validated emotional reactivity paradigm to identify differences between IBS patients and HCs in emotional arousal–related brain responses. When contrasting the brain's response to the negative emotional faces with the response to neutral geometric forms (ME-MF), consistent activations in amygdala, thalamus, and lateral prefrontal and parietal cortices, and deactivations in medial PFC, insula, and posterior cingulate cortex were seen. C/C genotype, regardless of diagnosis, was

Summary and Future Directions

By using a validated emotional reactivity paradigm, unrelated to the gastrointestinal system, we found significant correlations of the HTR3A c.-42C>T polymorphism with amygdala responsiveness, anxiety, and IBS symptom severity in a relatively small sample. The study supports the important role of 5-HT₃Rs in the modulation of emotional arousal circuits that previously have been shown to be related to 5-HT₃R antagonist-mediated (alosetron) IBS symptom improvement.¹³ These findings suggest that

Acknowledgments

B.N. and E.A.M. shared senior authorship of the article.

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: Conflicts of interest The authors disclose no conflicts.

: Funding This study was supported by National Institutes of Health grants DK 64539, DK 48351, and AT 002681.

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Clinical—Alimentary TractThe HTR3A Polymorphism c. -42C>T Is Associated With Amygdala Responsiveness in Patients With Irritable Bowel Syndrome

Background & Aims

Methods

Results

Conclusions

Section snippets

Subjects

HTR3A polymorphism

Discussion

Summary and Future Directions

Acknowledgments

Curr Opin Pharmacol

Eur J Pharmacol

Pharmacol Ther

Prog Neurobiol

Gastroenterology

Neuroimage

Neuropharmacology

Neuron

Behav Brain Res

Neuropharmacology

Pharmacol Ther

Neuroimage

Neuroimage

Drug Alcohol Depend

Biol Psychiatry

Neuroscience

Pharmacol Biochem Behav

Behav Brain Res

Behav Brain Res

Functional variants of the serotonin receptor type 3A and B gene are associated with eating disorders

Pharmacogenet Genomics

Two naturally occurring variants of the serotonin receptor gene HTR3C are associated with nausea in pregnancy

Acta Obstet Gynecol Scand

Alosetron and irritable bowel syndrome

Expert Opin Pharmacother

Options for patients with irritable bowel syndrome: contrasting traditional and novel serotonergic therapies

Neurogastroenterol Motil

A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS

Am J Gastroenterol

The auspicious role of the 5-HT3 receptor in depression: a probable neuronal target?

J Psychopharmacol

Understanding comorbidity with depression and anxiety disorders

J Am Osteopath Assoc

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