666 Corticotropin Releasing Hormone Receptor 1 (CRH-R1) and Progestoerone Receptor (PGR) Polymorphisms Interact With Early Life Trauma in Healthy Controls (HC) and Patients With Irritable Bowel Syndrome (IBS)

Abstract

BACKGROUND: Although studies have suggested genetic and environmental influences interact to contribute substantially to vulnerability to illness, the search for direct genetic x environmental influences contributing to the risk for IBS have been inconclusive so far. Genes regulating the effects of stress via the HPA axis have been implicated in the physiological and pathological regulation of stress reactivity as being mediated by release of hypothalamic corticotrophin releasing hormone (CRH). HPA activity is modulated by sex hormones progesterone and estrogen. HPA axis hyperactivity may be a function of psychosocial stressors such as early adverse life events (EALs) and may show sex-specific effects on emotional arousal circuitry in the brain. The hippocampus is a major component of the emotional arousal system and expresses CRH-R1, PGR and estrogen receptors (ESR1). AIMS: To examine gene-environment interactions on hippocampal volumes in male and female IBS patients and HCs. CRH-R1, PGR, and ESR1 polymorphisms were examined for effects on hippocampal volumes and interactions with early life trauma, sex, and diagnosis. METHODS: In a racially diverse community population of IBS and HCs, three SNPs of the CRH-R1 gene (rs7209436, rs110402, and rs242924), 2 SNPs of the PGR gene (rs1042838, rs10895068) and 1 SNP of the ESR1 gene (rs9340799) were genotyped. Subjects completed structural MRI scans and the volumes of the right and left hippocampus were computed. Haplotypes were created using Mendel software for each gene of interest and were analyzed in a linear regression model controlling for age, race, and total brain volume. We tested for main effects of genotype, sex, diagnosis, early life trauma index (ETI) as well as interactions between genotype and ETI with sex and diagnosis. RESULTS: 122 IBS patients (91 female) and 205 HCs (female 164) were studied. Significant Sex x Gene x ETI interactions were seen for PGR and CRH-R1 in the right hippocampus and for PGR in the left hippocampus. For males with PGR minor alleles, higher ETI was associated with smaller right and left hippocampal volumes, while no effect was seen in females. For males with CRH-R1 major alleles, higher ETI was associated with smaller right hippocampal volume. CONCLUSION: Sex differences in interactions between EALs and polymorphisms in genes directly involved or modulating the stress reactivity CRH system were demonstrated for volume of the hippocampus, a region involved in emotional arousal. Specifically, PGR and CRH-R1 demonstrated male-specific effects of ETI on hippocampal volume. Both PGR and CRH-R1 are expressed in the hippocampus. Progesterone is involved in neurogenesis and modulates HPA activity. The results highlight the importance of considering sex in examining gene-environment effects in IBS.