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Associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in systemic lupus erythematosus patients

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Abstract

Objectives

To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients.

Methods

All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case–control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses.

Results

rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, PBH = 0.037; rs9368878, PBH = 0.001; rs7757037, PBH = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (PBH = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (PBH = 0.022) and mental component summary (PBH = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all PBH = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (PBH = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety.

Conclusions

FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients.

Key Points

• FKBP5 gene polymorphisms were associated with depression of SLE patients.

• FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients.

• FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients.

• FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.

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Acknowledgments

We are grateful to all the participants for their enthusiastic participation in this research. This work was supported by the grant from the National Natural Science Foundation of China (81872683, 81673254, 81872687, 81573222).

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Author notes

  1. Qiu-Yue Lou, Zhen Li, Ying Teng contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, No. 81, Meishan Rd, Shushan District, Hefei, 230032, Anhui, China

    Qiu-Yue Lou, Zhen Li, Ying Teng, Qiao-Mei Xie, Man Zhang, Shun-Wei Huang, Fa-Ming Pan, Hai-Feng Pan, Hong Su & Yan-Feng Zou

  2. The Key Laboratory of Anhui Medical Autoimmune Diseases, Hefei, 230032, Anhui, China

    Qiu-Yue Lou, Zhen Li, Ying Teng, Qiao-Mei Xie, Man Zhang, Shun-Wei Huang, Fa-Ming Pan, Hai-Feng Pan, Hong Su & Yan-Feng Zou

  3. Department of Psychiatry, Anhui Mental Health Center, Hefei, 230022, Anhui, China

    Wen-Fei Li

  4. Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Yang-Fan Chen, Sheng-Qian Xu, Jing Cai & Shuang Liu

  5. Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, Anhui, China

    Jin-Hui Tao

  6. Institute of Dermatology and Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Sheng-Xiu Liu

  7. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui, China

    Hai-Liang Huang

  8. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Fang Wang

  9. School of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Victoria Park, Brisbane, Queensland, 4059, Australia

    Zhi-Wei Xu & Wen-Biao Hu

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  1. Qiu-Yue Lou
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Fig. S1

Schematic diagram of the interaction of GR with FKBP4/FKBP5. The body is stimulated by stress and transmitted to the hypothalamus, causing an increase in corticotropin-releasing hormone (CRH) secretion. CRH promotes the release of adrenocorticotropic hormone (ACTH) which enhances the release of cortisol (CORT) from the adrenal cortex. Subsequently, CORT binds to glucocorticoid receptor (GR) in the ligand complex, and the ligand complex is activated. Meanwhile, FKBP5 in the ligand complex is replaced by FKBP4, allowing GR to transfer to the nucleus and bind to DNA. That induces the expression of FKBP5 causing increased FKBP5 production, completing an ultra-short negative feedback loop on GR sensitivity. (PPTX 1836 kb).

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Lou, QY., Li, Z., Teng, Y. et al. Associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in systemic lupus erythematosus patients. Clin Rheumatol 40, 167–179 (2021). https://doi.org/10.1007/s10067-020-05195-0

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