5-HT3 receptor subunit type a gene (HTR3A) polymorphism is associated with anxiety and increased amygdala responsiveness in healthy controls and irritable bowel syndrome (IBS) patients

Abstract

Background: 5-HT3 receptor (5-HT3R) antagonists are effective in treating patients with several stress-sensitive persistent pain disorders (including IBS and fibromyalgia) and have anxiolytic effects. The therapeutic effect in IBS is related in part to reduced amygdala engagement during expected visceral pain (Berman et al, Gastroenterology 2002). The HTR3A single nucleotide polymorphism (SNP) c.-42C>T (C178T; rs1062613) is associated with altered amygdala reactivity during processing of neutral facial stimuli in healthy control subjects (HCs) (Iidaka et al, J Neurosci 2005). We aimed to evaluate the influence of this particular HTR3A SNP on amygdala reactivity to emotional facial stimuli and non-emotional visual stimuli in female HCs and IBS patients. Methods: Brain responses during a validated emotional reactivity task were measured in 55 female subjects (26 diagnosed with IBS) using fMRI (3.0 T). Subjects attended to the emotional expression (angry or fearful) of a target face in the Match Emotion condition (ME) and the shape of a target geometric form in the Match Form condition (MF). A region of interest analysis in SPM5 was used to examine the effect of the HTR3A c.-42C>T genotype (C/C vs. T carrier) on amygdala responsiveness in HCs and IBS patients. Results: Fifteen out of 29 HCs and 16 out of 26 IBS patients carried the C allele in a homocygous manner, nine HCs and seven patients carried the heterozygous C/T genotype, and five HCs and three patients carried the homozygous T/T genotype. Subjects carrying the T allele in either a homocygous or heterocygous manner (C/T+T/T) were combined into a single group ("T carriers") for analyses. Chi-square test indicated no significant association between T carrier status and diagnosis (p=.588). An ANOVA revealed a significant interaction of diagnosis and T carrier status on anxiety symptoms, with IBS patients reporting higher anxiety ratings, and T carriers (IBS and HCs combined) reporting lower anxiety ratings (F(1,51)=4.20, p=.046; F(1,51)=4.37, p=.042, respectively). Within IBS patients, C/C genotype subjects demonstrated greater overall symptom severity (t(24)=2.102, p=.046) and abdominal discomfort (bloating) ratings (t(24)=2.654, p=.014) but did not differ in abdominal pain ratings (p>.05). Consistent with previous studies, the emotional reactivity task activated bilateral amygdala across all subjects, while no diagnosis or genotype effects on amygdala emotional reactivity (ME-MF) were found. However, C/C genotype subjects, regardless of diagnosis, demonstrated greater amygdala activity during both the ME and MF conditions when considered separately (p's T polymorphism, compared to T carrier status is associated with increased anxiety and a generalized hyper-responsiveness of the amygdala. While this particular genotype is not required for a diagnosis of IBS, it plays a role in the expression of symptom severity. In addition, a subset of IBS patients with C/C genotype demonstrated an extreme pattern of generalized amygdala hyper-responsiveness, failing to discriminate between emotional and neutral stimuli due to heightened responses during the non-emotional condition. Our findings suggest that the C/C genotype predisposes individuals to a state of indiscriminant hypervigilance, especially in IBS patients. Subtyping of IBS patients based on gene variants of central receptors modulating emotional arousal may therefore improve the outcome of future clinical trials.