FK506 binding protein 5 (FKBP5) gene polymorphisms and their relationship with pharmacological response in bipolar disorders

Scaini et al. offer an informative review of current knowledge about the neurobiology of bipolar disorders,¹ discussing the over-expression of FK506-binding protein 51 (FKBP51) as a putative mechanism conferring increased risk of mood dysregulation in bipolar disorders.

FKBP51 is involved in the hypothalamic pituitary axis feedback loop by acting as a co-chaperone for the sensitivity of the glucocorticoid receptor.¹ This mechanism is of importance because FKBP51 could decrease the glucocorticoid receptor’s affinity for circulating glucocorticoids and help explain the dysfunctional negative feedback of the hypothalamic pituitary axis, which could be responsible for the increased vulnerability to mood episodes in bipolar disorders.¹,²

FKBP51 is expressed by the FKBP5 gene, which is located on chromosome 6p21.²,³ FKBP5 has been shown to be involved in the etiology of mood disorders, as well as in susceptibility to treatment response in mood disorders.² Certain FKBP5 allele variants have been associated with exaggerated expression of the FKBP5 gene, resulting in FKBP51 over-expression. Three high induction alleles of major FKBP5 gene polymorphisms are believed to enhance FKBP5 mRNA expression following glucocorticoid receptor activation, including rs1360780 (T-allele), rs3800373 (C-allele), and rs4713916 (A-allele).³

In order to confirm previous reports³ of the role of FKBP5 high induction alleles, a systematic search of the literature on bipolar disorders, including PubMed, EMBASE, PsycINFO, Cochrane Library and Ovid MEDLINE, was conducted to identify studies that investigated FKBP5 polymorphisms in relation to treatment response in mood disorders. Studies were included if: 1) patients had mood disorders; 2) the disorders were diagnosed according to DSM or ICD classification systems; 3) the design was longitudinal; and 4) assessed response according to validated rating scales, expressed as odd ratios and 95% confidence intervals (95%CI). Eight studies met the criteria and included patients with unipolar and bipolar disorders, which allowed comparison between high and low induction alleles (detailed information available upon request via [e-mail]).

A random effects model meta-analysis was conducted in STATA to create a summary effect size and assess publication bias to investigate the relationship between high induction FKBP5 single nucleotide polymorphisms rs1360780, rs3800373, and rs4713916 and treatment response in mood disorders. The analysis of the rs4713916 FKBP5 A-high induction allele, obtained by combining three samples (two included patients with bipolar disorders),⁴,⁵ indicated that carriers of this polymorphism are more likely to respond to treatment in mood disorders (effect size: 1.28; 95%CI 1.04-1.57). The analysis was free of heterogeneity (χ² = 1.01, degrees of freedom = 2, p = 0.6) and publication bias (Coef = 0.16, p = 0.3) (Figure 1). Analyses of the other two high induction alleles of FKBP5 polymorphisms showed no significant effect (rs1360780 effect size: 1.19; 95%CI 0.87-1.62; and rs3800373 effect size: 1.22; 95%CI 0.86-1.72) in the absence of publication bias (all p-values > 0.05).

Figure 1
Meta-analysis of rs4713916 FKBP5 A-high induction allele.

The results suggest that the high induction allele of rs4713916 in FKBP5 might increase susceptibility to treatment response in mood disorders. Further work is required to more clearly determine the role of FKBP5 rs4713916 in bipolar disorders.

Acknowledgements

The author would like to acknowledge Nabiha Essaji's contribution in retrieving the information for the analyses (studentship program at King’s College London).

References

• ¹
  Scaini G, Valvassori SS, Diaz AP, Lima CN, Benevenuto D, Fries GR, et al. Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings. Braz J Psychiatry. 2020 Apr 3;S1516-44462020005007202. doi: http://10.1590/1516-4446-2019-0732 Online ahead of print.
  » http://10.1590/1516-4446-2019-0732
• ²
  Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34 Suppl 1:S186-95.
• ³
  Zou YF, Wang F, Feng XL, Li WF, Tao JH, Pan FM, et al. Meta-analysis of FKBP5 gene polymorphisms association with treatment response in patients with mood disorders. Neurosci Lett. 2010;484:56-61.
• ⁴
  Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004;36:1319-25.
• ⁵
  Lekman M, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, et al. The FKBP5-gene in depression and treatment response--an association study in the sequenced treatment alternatives to relieve depression (STAR*D) cohort. Biol Psychiatry. 2008;63:1103-10.

Publication Dates

• Publication in this collection
  18 Sept 2020
• Date of issue
  Jan-Feb 2021

History

• Received
  14 June 2020
• Accepted
  25 June 2020