Serotonin Transporter Gene Polymorphism Modulates Activity and Connectivity within an Emotional Arousal Network of Healthy Men during an Aversive Visceral Stimulus.

Background and aimsThe 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) has been linked to increased stress responsiveness and negative emotional states. During fearful face recognition individuals with the s allele of 5-HTTLPR show greater amygdala activation. We aimed to test the hypothesis that the 5-HTTLPR polymorphism differentially affects connectivity within brain networks during an aversive visceral stimulus.MethodsTwenty-three healthy male subjects were enrolled. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Subjects with the s/s genotype (n = 13) were compared to those with the l allele (genotypes l/s, l/l, n = 10). Controlled rectal distension from 0 to 40 mmHg was delivered in random order using a barostat. Radioactive H2[15-O] saline was injected at time of distension followed by positron emission tomography (PET). Changes in regional cerebral blood flow (rCBF) were analyzed using partial least squares (PLS) and structural equation modeling (SEM).ResultsDuring baseline, subjects with s/s genotype demonstrated a significantly increased negative influence of pregenual ACC (pACC) on amygdala activity compared to l-carriers. During inflation, subjects with s/s genotype demonstrated a significantly greater positive influence of hippocampus on amygdala activity compared to l-carriers.ConclusionIn male Japanese subjects, individuals with s/s genotype show alterations in the connectivity of brain regions involved in stress responsiveness and emotion regulation during aversive visceral stimuli compared to those with l carriers

Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome.

Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs) of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220) were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale.We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017) and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS), and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710) and two SNPs (rs2284217 and rs2284220) in strong linkage disequilibrium (D' > 0.90). We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion.Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH system are warranted

Serotonin Transporter Gene Polymorphism Modulates Activity and Connectivity within an Emotional Arousal Network of Healthy Men during an Aversive Visceral Stimulus.

Background and aimsThe 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) has been linked to increased stress responsiveness and negative emotional states. During fearful face recognition individuals with the s allele of 5-HTTLPR show greater amygdala activation. We aimed to test the hypothesis that the 5-HTTLPR polymorphism differentially affects connectivity within brain networks during an aversive visceral stimulus.MethodsTwenty-three healthy male subjects were enrolled. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Subjects with the s/s genotype (n = 13) were compared to those with the l allele (genotypes l/s, l/l, n = 10). Controlled rectal distension from 0 to 40 mmHg was delivered in random order using a barostat. Radioactive H2[15-O] saline was injected at time of distension followed by positron emission tomography (PET). Changes in regional cerebral blood flow (rCBF) were analyzed using partial least squares (PLS) and structural equation modeling (SEM).ResultsDuring baseline, subjects with s/s genotype demonstrated a significantly increased negative influence of pregenual ACC (pACC) on amygdala activity compared to l-carriers. During inflation, subjects with s/s genotype demonstrated a significantly greater positive influence of hippocampus on amygdala activity compared to l-carriers.ConclusionIn male Japanese subjects, individuals with s/s genotype show alterations in the connectivity of brain regions involved in stress responsiveness and emotion regulation during aversive visceral stimuli compared to those with l carriers

Psychological scale scores and <i>CRHR2</i> haplotypes.

<p>The psychological scales PSS (A), STAI (state) (B), STAI (trait) (C) and SDS (D) were shown. One-way ANOVA showed that the subjects with four haplotypes (T-T-T-T, C-T-T-T, C-C-T-T, and T-C-T-T) had significantly lower score than the others in all psychological scales. The four haplotype carriers were all the same individuals. In addition, in PSS, two haplotypes (C-T-C-T and C-C-C-T) were similarly significant.</p

Psychological scales and <i>CRHR2</i> SNPs in IBS patients and controls.

<p>PSS: two-way ANOVA showed that the IBS patients with <i>rs2240403</i> (<i>P</i> = 0.018) had significantly higher perceived stress scale scores than the controls. STAI (state): <i>rs2190242</i> in males, genotype effect was significant (<i>P</i> = 0.046). SDS: <i>rs2190242</i> in males and <i>rs2240403</i> in females, genotype effect was significant (<i>rs2190242</i>: <i>P</i> = 0.026; <i>rs2240403</i>: <i>P</i> = 0.031). In all scale scores, there was no significant group × genotype interaction.</p

Difference in genotype of <i>CRHR2</i> SNPs between the controls and IBS patients.

<p>The SNPs <i>rs4722999</i> (<b>A</b>) and <i>rs3779250</i> (<b>B</b>) are shown. The SNPs <i>rs4722999</i> (<i>P</i> = 0.037) and <i>rs3779250</i> (<i>P</i> = 0.017, χ²-test) were significantly different in the IBS patients in comparison with the controls.</p

SNPs of the <i>CRHR2</i> gene examined in this study.

<p><i>CRHR2</i> is located on chromosome 7p14.3. The arrows and the numbers in parentheses indicate the locus of each SNP. <i>rs2240403</i> exists in the fourth exon, but six other SNPs exist in intronic regions. These SNPs had a minor allele frequency of >15% in the Japanese population. A linkage disequilibrium (LD) plot was generated using D′. D′ = 1 indicates complete LD. D′ values < 1.0 are shown in the respective squares for the SNP pairs, with darker shades of red representing higher levels of LD.</p

Connectivity Analysis for Baseline and Colorectal Distention.

<p>Chi square difference statistics during baseline and colorectal distention. λ² difference > 3.84 is considered significant and is denoted in red. λ² difference < 3.84 is considered non-significant and is denoted in blue. Regions: AMYG, amygdala; HIPP, hippocampus, sgACC, subgenual cingulate cortex; pACC, pregenual anterior cingulate cortex; mPFC, medial prefrontal cortex; dlPFC, dorsolateral prefrontal cortex; vlPFC, ventro-lateral prefrontal cortex; aMCC, anterior mid cingulate cortex; PCC, posterior cingulate cortex; aINS, anterior insula; mINS, mid insula; pINS, posterior insula.</p

Activations and deactivations within a network distinguishing inflation from non-Iinflation that is engaged to a greater extent in subjects with <i>s/s</i> genotype compared to <i>l</i>-carriers.

<p>Abbreviations: BA, Brodmann area; PHG, parahippocampal gyrus.</p><p>Activations and deactivations within a network distinguishing inflation from non-Iinflation that is engaged to a greater extent in subjects with <i>s/s</i> genotype compared to <i>l</i>-carriers.</p

Location of seed voxels for SEM.

<p>Abbreviations: sgACC, subgenual cingulate cortex; pACC, pregenual anterior cingulate cortex; mPFC, medial prefrontal cortex; vlPFC, ventro-lateral prefrontal cortex; dlPFC, dorsolateral prefrontal cortex</p><p>Location of seed voxels for SEM.</p