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

Abstract

BACKGROUND Corticotropin-releasing hormone receptor 1 (CRH-R1) in the amygdala and the stria terminalis plays an important role in the activation of central stress circuits. Genetic factors may contribute to the hyperresponsiveness of these circuits in irritable bowel syndrome (IBS). AIMS To determine if CRH-R1 SNPs are associated with: 1) a diagnosis of IBS, 2) gastrointestinal (GI) symptoms, and 3) acoustic startle response (ASR) to threat, which is mediated by the amygdala via CRH. METHODS Three CRH-R1 SNPS (rs110402, rs242924, and rs7209436) were genotyped using salivary DNA from IBS and healthy control subjects (HCs). Eye blink ASR was obtained during safe (no shock), anticipation (abdominal shock may soon occur) and threat (abdominal shock likely) conditions in a subset of subjects. Associations between each SNP with IBS status, clinical traits and ASR were measured. RESULTS 235 IBS patients (mean age 37.5 yrs, 74% F) and 264 HCs (mean age 32.1 yrs, 70% F) were studied. Of these, 57 IBS and 41 HCs underwent the ASR protocol. The presence of IBS was associated with the major allele for all three CRH-R1 SNPs (p=0.009-0.025). Within IBS, the major allele for all three SNPs (p=0.017-0.065) was associated with GI symptom anxiety scores. Within subjects with at least one copy of the major allele for the CRH-R1 SNPs, IBS had significantly lower ASR compared to HCs during threat conditions (p=0.001-0.002). Within IBS, CRH-R1 SNPs were associated with a graded increase in ASR to threat (p=0.007-0.008). CONCLUSION These findings support that CRH-R1 contributes to the dysregulated stress responsiveness in IBS.

Evidence-based clinical practice guidelines for irritable bowel syndrome 2020

“…Another meta-analysis showed a decreased risk of IBS in subjects with the l/s gene and increased risk of IBS-C in those with the s/s gene as well as populational differences between Asian and EU/US cohorts [ 53 ]. Some associations between IBS and CRH-related genes (CRH, CRH binding protein [ 54 ], CRH-R1 [ 55 ], and CRH-R2 [ 56 ]) were identified and replicated [ 57 ].…”

Vitamin D3 Supplementation in Diarrhea-Predominant Irritable Bowel Syndrome Patients: The Effects on Symptoms Improvement, Serum Corticotropin-Releasing Hormone, and Interleukin-6 – A Randomized Clinical Trial

“…CRH increases in the serum of patients with IBS and can cause diarrhea by increasing intestinal movements through its receptor (CRHR1) in response to anxiety [8, 9]. In addition, peripheral inflammation stimulates the release of CRH by upregulation of ACTH production, which is an indication of IBS symptoms [38].…”

“…CRHR2 has a completely opposite function compared to CRHR1 [11]. CRHR1 is mostly found in the myenteric plexus, and prescription of a CRHR1 antagonist in IBS patients can suppress colonic movements and abdominal pain [9]. Low-grade inflammation is observed in the intestinal epithelium of patients with IBS [11].…”

“…Corticotropin-releasing hormone (CRH) is released from the paraventricular nucleus of the hypothalamus in response to stress conditions. Elevated CRH leads to increased bowel movements, intestinal permeability, and activity of the immune system in IBS patients [8, 9]. CRH has two receptors which are mainly located in the brain; however, they are also located in other organs, including smooth muscle cells in the GI tract.…”

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

“…Second, the major alleles of CRHR1 rs110402, rs242924 and rs720943 (all C) were associated with increased risk for IBS and, within IBS patients, increased GI-symptom-related anxiety. Unexpectedly, IBS patients with the same risk alleles showed reduced acoustic startle responses vs. healthy controls, whereas those with the minor alleles did not, indicating a complex influence of the CRHR1 SNPs on different symptoms of anxiety per diagnostic group (Orand et al 2016). Finally, a separate study of young Japanese individuals observed that the CRHR1 rs10474485 locus was associated with increased psychometric scores for depression, perceived stress or state/trait anxiety in IBS patients with diarrhea or mixed symptoms, with the CRHR1 variant more predictive of differences in emotional scales in women than in men (Sasaki et al 2016).…”