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

Abstract

BackgroundCorticotropin-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.MethodsA 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.ResultsWe 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.ConclusionOur 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.

The Increased Level of Depression and Anxiety in Irritable Bowel Syndrome Patients Compared with Healthy Controls: Systematic Review and Meta-analysis

“…[10][11][12][13][15][16][17][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] The baseline characteristics of included studies are shown in Table 1 22,29 Sphere score in 1 study, 24 and the Beck Anxiety Inventory (BAI) in 1 study. 30 …”

“…2B). 11,13,22,25,28,29,34,36 However, 4 of 8 outlier studies were age-sex (hyphen) unmatched. 13,28,29,34 The Anxiety Level in Irritable Bowel Syndrome Patients…”

“…3B). 10,11,13,22,25,28,29,35,36 Meta-regression Analysis and Sub-group Analysis Meta-regression analysis was conducted due to medium and high heterogeneity. The result of meta-regression is shown in Table 2.…”

“…1,4,9 Animal studies have demonstrated the influence of stress on colonic permeability, and mucosal and systemic inflammation's mediation by the autonomic nervous system and the hypothalamo-pituitary-adrenal axis. 4 Several recently published studies have mapped IBS's relationship with psychological disorders [10][11][12][13][14][15][16] and compared depression and anxiety levels in IBS-subtypes. 15,17,18 However, the relationship between IBS and psychological disorders (depression or anxiety) was inconsistent, even in a recent meta-analysis entailing eight studies.…”

Corticotropin-releasing hormone receptor 1 (CRH-R1) polymorphisms are associated with irritable bowel syndrome and acoustic startle response

“…103 IBS and 142 healthy controls. This group subsequently measured associations of IBS status with CRH SNPs in 111 IBS and 142 controls (Sasaki et al, 2016) and CRH receptor 2 (CRH-R2) SNPs (Komuro et al, 2016) in 142 IBS and 142 controls in a Japanese population. CRH-R2 SNP, but not CRH SNP, associations with the presence of IBS were found.…”