Association of SNPs in the FK-506 binding protein ( <i>FKBP5</i>) gene among Han Chinese women with polycystic ovary syndrome

Author(s): Xinyue Ma ¹ ^, ² ^, ³ ^, ⁴ , Zhao Wang ¹ ^, ² ^, ³ ^, ⁴ , Changming Zhang ¹ ^, ² ^, ³ ^, ⁴ , Yuehong Bian ¹ ^, ² ^, ³ ^, ⁴ , Xin Zhang ¹ ^, ² ^, ³ ^, ⁴ , Xin Liu ⁵ , Yongzhi Cao ¹ ^, ² ^, ³ ^, ⁴ ^, , Yueran Zhao ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^,

Publication date (Electronic): 4 July 2022

Journal: BMC Medical Genomics

Publisher: BioMed Central

Keywords: PCOS, Hyperandrogenism, FKBP5, SNP, Association

Read this article at

ScienceOpen Publisher PMC

Bookmark

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women, whose etiology remains uncertain, although it is known to be highly heterogeneous and genetically complex. PCOS often presents with hyperandrogenism symptoms. The present study aimed to determine whether polymorphisms in the FK-506 binding protein 5 ( FKBP5) gene (androgen target gene) are associated with an association for PCOS and hyperandrogenism.

Methods

This is a case–control study, and association analyses were conducted. A total of 13 single-nucleotide polymorphisms (SNPs) in the FKBP5 gene were evaluated in 775 PCOS patients who were diagnosed based on the Rotterdam Standard and 783 healthy Chinese Han women. Associations between FKBP5 SNPs and hormone levels were investigated. These 13 SNPs were genotyped using the Sequenom MassARRAY system, and an association analysis between the phenotype and alleles and genotypes were conducted.

Results

The genotype frequencies for the rs1360780 and rs3800373 SNPs differed significantly between the PCOS cases and healthy controls (p = 0.025, OR is 1.63 (1.05–2.53) and p = 0.029, OR is 1.59 (1.03–2.45) respectively under co-dominant model). Moreover, the genotype frequencies and genetic model analysis for the SNPs rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037 differed significantly between the hyperandrogenism and non-hyperandrogenism groups of PCOS patients. The TT genotype of rs1360780, the TT genotype of rs9470080, the TT genotype of rs1043805 or the GG genotype of rs7705037 (ORs are 2.13 (1.03–4.39), 1.81 (1.03–3.17), 2.94 (1.32–6.53) and 1.72 (1.04–2.84) respectively) were correlated with androgen level of PCOS patients.

Conclusion

Our study showed that FKBP5 gene polymorphisms are associated with PCOS generally (rs1360780 and rs3800373) and with the hyperandrogenism subtype specifically (rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037).

Supplementary Information

The online version contains supplementary material available at 10.1186/s12920-022-01301-0.

Related collections

Most cited references 48

Record: found
Abstract: found
Article: not found

Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.

Torsten Klengel, Divya Mehta, Christoph Anacker … (2013)

Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

0 comments Cited 443 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

Robert Rosenfield, David A Ehrmann (2016)

Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.

0 comments Cited 396 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome.

Daniel Dumesic, Sharon Oberfield, Elisabet Stener-Victorin … (2015)

Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown.

0 comments Cited 228 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Yongzhi Cao: yz_cao@163.com

Yueran Zhao: yrzhao@sdu.edu.cn

Journal

Journal ID (nlm-ta): BMC Med Genomics

Journal ID (iso-abbrev): BMC Med Genomics

Title: BMC Medical Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1755-8794

Publication date (Electronic): 4 July 2022

Publication date PMC-release: 4 July 2022

Publication date Collection: 2022

Volume: 15

Electronic Location Identifier: 149

Affiliations

[1 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Center for Reproductive Medicine, Cheeloo College of Medicine, , Shandong University, ; Jinan, 250012 Shandong China

[2 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, , Shandong University, ; Jinan, 250012 Shandong China

[3 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Key Laboratory of Reproductive Endocrinology of Ministry of Education, , Shandong University, ; Jinan, 250012 Shandong China

[4 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Shandong Provincial Clinical Medicine Research Center for Reproductive Health, , Shandong University, ; Jinan, 250012 Shandong China

[5 ]GRID grid.27255.37, ISNI 0000 0004 1761 1174, Central Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, , Shandong University, ; Jinan, 250021 Shandong China

Article

Publisher ID: 1301

DOI: 10.1186/s12920-022-01301-0

PMC ID: 9254403

PubMed ID: 35787810

SO-VID: 1659645e-6669-4de0-b85c-a60db853469b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 14 October 2021

Date accepted : 30 June 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100012166, National Key Research and Development Program of China;

Award ID: 2017YFC1001002

Award Recipient : Xinyue Ma Zhao Wang Changming Zhang Yuehong Bian Xin Zhang Xin Liu Yongzhi Cao Yueran Zhao

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: pcos,hyperandrogenism,fkbp5,snp,association

Data availability:

ScienceOpen disciplines: Genetics

Keywords: pcos, hyperandrogenism, fkbp5, snp, association

Comments

Comment on this article

scite_

Cited by 3

See all cited by

Most referenced authors 507

See all reference authors

Association of SNPs in the FK-506 binding protein ( FKBP5) gene among Han Chinese women with polycystic ovary syndrome

Read this article at

Abstract

Background

Methods

Results

Conclusion

Supplementary Information

Related collections

Genes & Diseases

Most cited references 48

Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.

The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome.

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 626

Cited by 3

Most referenced authors 507