Novel corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) linkage to and association with polycystic ovary syndrome.

Female Humans Corticotropin-Releasing Hormone / genetics Diabetes Mellitus, Type 2 Hypothalamo-Hypophyseal System / metabolism Polycystic Ovary Syndrome / genetics Receptors, Corticotropin-Releasing Hormone / genetics
Association CRHR Corticotropin-releasing hormone receptor Cortisol Gene HPA-axis Hypothalamic–pituitary–adrenal axis Infertility Ovary PCOS Polycystic ovarian syndrome

Journal

Journal of ovarian research
ISSN: 1757-2215
Titre abrégé: J Ovarian Res
Pays: England
ID NLM: 101474849

Informations de publication

Date de publication:
05 Aug 2023
Historique:
received: 27 11 2022
accepted: 10 04 2023
medline: 7 8 2023
pubmed: 6 8 2023
entrez: 5 8 2023
Statut: epublish

Résumé

Women with polycystic ovarian syndrome (PCOS) have increased hypothalamic-pituitary-adrenal (HPA) axis activation, pro-inflammatory mediators, and psychological distress in response to stressors. In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in CRHR1 and CRHR2 genes may predispose to the mental-metabolic risk for PCOS. We phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within CRHR1 and CRHR2 genes, respectively, 36 and 18 microarray-variants for parametric linkage to and/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2). We detected 22 variants in CRHR1 and 1 variant in CRHR2 significantly (p < 0.05) linked to or in LD with PCOS across different inheritance models. This is the first study to report CRHR1 and CRHR2 as novel risk genes in PCOS. In silico analysis predicted that the detected CRHR1 and CRHR2 risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, CRHR1- and CRHR2-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.

Sections du résumé

BACKGROUND BACKGROUND
Women with polycystic ovarian syndrome (PCOS) have increased hypothalamic-pituitary-adrenal (HPA) axis activation, pro-inflammatory mediators, and psychological distress in response to stressors. In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in CRHR1 and CRHR2 genes may predispose to the mental-metabolic risk for PCOS.
METHODS METHODS
We phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within CRHR1 and CRHR2 genes, respectively, 36 and 18 microarray-variants for parametric linkage to and/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2).
RESULTS RESULTS
We detected 22 variants in CRHR1 and 1 variant in CRHR2 significantly (p < 0.05) linked to or in LD with PCOS across different inheritance models.
CONCLUSIONS CONCLUSIONS
This is the first study to report CRHR1 and CRHR2 as novel risk genes in PCOS. In silico analysis predicted that the detected CRHR1 and CRHR2 risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, CRHR1- and CRHR2-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.

Identifiants

DOI: 10.1186/s13048-023-01159-5 PMID: 37543650 PMC: PMC10403835
pubmed: 37543650
doi: 10.1186/s13048-023-01159-5
pii: 10.1186/s13048-023-01159-5
pmc: PMC10403835
doi:

Substances chimiques

Corticotropin-Releasing Hormone 9015-71-8
Receptors, Corticotropin-Releasing Hormone 0
CRF receptor type 1 5CLY6W2H1M
CRF receptor type 2 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

155

Subventions

Organisme : Nebraska Department of Health and Human Services
ID : Funds received under Nebraska Laws 2021, LB 380, Section 109

Informations de copyright

© 2023. BioMed Central Ltd., part of Springer Nature.

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Auteurs

Mutaz Amin (M)

INSERM, US14-Orphanet, 75014, Paris, France.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum, Sudan, 11121.

Nicholas Horst (N)

Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USA.

Rongling Wu (R)

Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA.
Department of Statistics, Penn State College of Medicine, Hershey, PA, 17033, USA.

Claudia Gragnoli (C)

Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USA. claudia.gragnoli@gmail.com.
Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA. claudia.gragnoli@gmail.com.
Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, 00197, Rome, Italy. claudia.gragnoli@gmail.com.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Novel corticotropin-releasing hormone receptor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Neuropeptides › Hormones hypothalamiques › Hormones hypophysiotropes libératrices › Corticolibérine › Novel corticotropin-releasing hormone receptor...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Diabète de type 2 › Novel corticotropin-releasing hormone receptor...
questionsmedicales.fr › Système nerveux › Système neuroendocrinien › Axe hypothalamohypophysaire › Novel corticotropin-releasing hormone receptor...
questionsmedicales.fr › Maladies endocriniennes › Troubles gonadiques › Maladies ovariennes › Kystes de l'ovaire › Syndrome des ovaires polykystiques › Novel corticotropin-releasing hormone receptor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur hormones hypothalamiques hypophysotropes régulatrices › Récepteur CRH › Novel corticotropin-releasing hormone receptor...