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

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/Cgenotype. 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.