Interleukin-6 promoter polymorphism interacts with pain and life stress influencing depression phenotypes.

David Kovacs,Szilvia Vas,Peter Petschner,Nora Eszlari,Peter Kovacs,Xenia Gonda,Gabriella Juhasz,Gyorgy Bagdy,Dorottya Pap

doi:10.1007/s00702-016-1506-9

Abstract

Interleukin-6 (IL-6) has emerged as a potent biomarker for depression as its elevated plasma levels in patients with clinical depression have been confirmed by meta-analyses. Increased plasma IL-6 concentration was associated with various psychological stress factors and physical disorders accompanied by pain. Another modulator of the IL-6 level is rs1800795, a promoter polymorphism in the IL-6 gene which is able to influence its expression rate. Therefore, we examined in a Hungarian population sample of 1053 volunteers with European origins if rs1800795 polymorphism can affect depression symptoms measured by Zung Self-rating Depression Scale (ZSDS), and Brief Symptom Inventory (BSI). We also investigated the interactions of the polymorphism with reported painful physical conditions and Recent Negative Life Events (RLE) measured by the List of Life Threatening Experiences. Rs1800795 significantly interacted with both RLE and painful condition on depressive symptoms measured by ZSDS and BSI using different heritability models, while no main effects of the polymorphism were identified. After correction for multiple testing only the rs1800795 × RLE interaction effect (recessive model) remained significant on the BSI score, while both RLE and painful conditions significantly interacted on the ZSDS. In conclusion, the functional IL-6 rs1800795 polymorphism in interaction with various stress factors increases the risk of depression and has a greater impact on symptoms measured by the ZSDS. Thus, IL-6 and other cytokines may be more relevant in the development of somatic symptoms compared to affective signs of depression, delineating a specific genotype–phenotype relationship in this heterogeneous disorder.

Highlights

Apart from the evident involvement of monoamine neurotransmitter disturbances in depression, pro-inflammatory cytokine levels were repeatedly reported to be increased in depressed individuals compared to control subjects with meta-analyses supporting this observation (Dowlati et al 2010; Howren et al 2009)
We examined in a Hungarian population sample of 1053 volunteers with European origins if rs1800795 polymorphism can affect depression symptoms measured by Zung Self-rating Depression Scale (ZSDS), and Brief Symptom Inventory (BSI)
We examined the polymorphism’s interaction with Recent Negative Life events (RLE) and Pain Background (PBGR) information reported by the subjects

Summary

Introduction

Apart from the evident involvement of monoamine neurotransmitter disturbances in depression, pro-inflammatory cytokine levels were repeatedly reported to be increased in depressed individuals compared to control subjects with meta-analyses supporting this observation (Dowlati et al 2010; Howren et al 2009). The risk of developing depression during IFN treatment was found to be dependent on a functional polymorphism in the interleukin-6 (IL6) gene, rs1800795 (Udina et al 2013). The more recent reports were inconsistent about which allele of the polymorphism causes higher expression rates (Fife et al 2005; Kelberman et al 2004; Terry et al 2000). In spite of these controversies, the involvement of the rs1800795 polymorphism in the development of various disorders such as Alzheimer’s disease (Faltraco et al 2003), schizophrenia (Zakharyan et al 2012), and cerebral palsy (Wu et al 2011) was supported

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Conclusion