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

Hazuki Komuro; Naoko Sato; Ayaka Sasaki; Naoki Suzuki; Michiko Kano; Yukari Tanaka; Yumi Yamaguchi-Kabata; Motoyori Kanazawa; Hitoshi Warita; Masashi Aoki; Shin Fukudo

doi:10.1371/journal.pone.0147817

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

PLoS One. 2016 Jan 25;11(1):e0147817. doi: 10.1371/journal.pone.0147817. eCollection 2016.

Authors

Hazuki Komuro¹, Naoko Sato¹, Ayaka Sasaki¹, Naoki Suzuki², Michiko Kano^{1

3}, Yukari Tanaka^{1

4}, Yumi Yamaguchi-Kabata^{4

5}, Motoyori Kanazawa¹, Hitoshi Warita², Masashi Aoki², Shin Fukudo^{1

6}

Affiliations

¹ Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
² Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
³ Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan.
⁴ Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
⁵ Graduate School of Medicine, Tohoku University, Sendai, Japan.
⁶ Department of Psychosomatic Medicine, Tohoku University Hospital, Sendai, Japan.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Case-Control Studies
Female
Humans
Irritable Bowel Syndrome / genetics*
Male
Polymorphism, Single Nucleotide
Receptors, Corticotropin-Releasing Hormone / genetics*
Young Adult

Substances

CRF receptor type 2
Receptors, Corticotropin-Releasing Hormone

Associated data

figshare/10.6084/M9.FIGSHARE.1543516

Grants and funding

This research was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan, No. 15H04799, 15H15267 (http://www.mext.go.jp/english/), and Grant-in-Aid for Scientific Research from the Ministry of Health, Welfare, and Labor of Japan (26-4). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.