TY - JOUR
T1 - Novel corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) linkage to and association with polycystic ovary syndrome
AU - Amin, Mutaz
AU - Horst, Nicholas
AU - Wu, Rongling
AU - Gragnoli, Claudia
N1 - Funding Information:
We thank the families who participated in the study, and we thank Bios Biotech Multi-Diagnostic Health Center, Rome, Italy, for data access and for financial, medical, and laboratory staff support. This publication was supported in part with the funds received under Nebraska Laws 2021, LB 380, Section 109 awarded to C.G. (PI), Creighton University School of Medicine, through the Nebraska Department of Health & Human Services (DHHS). Its contents represent the views of the authors and do not necessarily represent the official views of the State of Nebraska or DHHS.
Funding Information:
We thank the families who participated in the study, and we thank Bios Biotech Multi-Diagnostic Health Center, Rome, Italy, for data access and for financial, medical, and laboratory staff support. This publication was supported in part with the funds received under Nebraska Laws 2021, LB 380, Section 109 awarded to C.G. (PI), Creighton University School of Medicine, through the Nebraska Department of Health & Human Services (DHHS). Its contents represent the views of the authors and do not necessarily represent the official views of the State of Nebraska or DHHS.
Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - 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: 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: 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: 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.
AB - 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: 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: 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: 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.
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U2 - 10.1186/s13048-023-01159-5
DO - 10.1186/s13048-023-01159-5
M3 - Article
C2 - 37543650
AN - SCOPUS:85166599280
SN - 1757-2215
VL - 16
JO - Journal of Ovarian Research
JF - Journal of Ovarian Research
IS - 1
M1 - 155
ER -
