Investigating the Epigenetic Profile of the Inflammatory Gene IL-6 in Late-life Depression

Overview

Journal BMC Psychiatry

Publisher Biomed Central

Specialty Psychiatry

Date 2017 Oct 27

PMID 29070016

Citations 19

Authors

Joanne Ryan

Lauren Pilkington

Katharina Neuhaus

Karen Ritchie

Marie-Laure Ancelin

Richard Saffery

Affiliations

Soon will be listed here.

Abstract

Background: It is well established that there is a link between inflammation and depression, with several studies reporting increased circulating levels of the pro-inflammatory cytokine, interleukin-6 (IL6), in depressed individuals. Peripheral epigenetic marks, including DNA methylation, hold promise as biomarkers for a range of complex conditions, with potential to inform diagnosis and tailor interventions. The aim of this study was to determine whether individuals with depression display differential methylation of the IL6 gene promoter compared to individuals without depression.

Methods: The ESPRIT study of later life neuropsychiatric disorders used a random sampling framework to select non-institutionalised participants aged ≥65 years and over living in the Montpellier region of France. Major depressive disorder (MDD) was assessed using the Mini International Neuropsychiatric Interview (MINI) according to DSM-IV criteria. High levels of depressive symptoms were defined as a score of ≥16 on the Centre for Epidemiologic Studies Depression Scale (CES-D). IL6 promoter DNA methylation was measured on a sub-sample of 380 participants who provided buccal samples.

Results: Individuals with depression (current MDD or high depressive symptoms) had lower IL6 methylation levels at one of the four sites investigated, however the effect size was small (∆ 2.4%, SE 0.009, p = 0.006). Interestingly, antidepressant use was independently associated with higher IL-6 methylation at the same site (∆ 4.6%, SE 0.019, p = 0.015). In multivariate linear regression analyses adjusting for covariates, including sex and smoking status, these associations remained. There was no effect modification when considering IL6 genotype.

Conclusion: This study presents evidence that IL6 methylation may be a marker of depression status in older individuals, however further work is now needed to replicate these findings and to assess the association with inflammatory status of individuals.

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References

Coolen M, Statham A, Gardiner-Garden M, Clark S . Genomic profiling of CpG methylation and allelic specificity using quantitative high-throughput mass spectrometry: critical evaluation and improvements. Nucleic Acids Res. 2007; 35(18):e119. PMC: 2094090. DOI: 10.1093/nar/gkm662. View

Lolak S, Suwannarat P, Lipsky R . Epigenetics of depression. Prog Mol Biol Transl Sci. 2014; 128:103-37. DOI: 10.1016/B978-0-12-800977-2.00005-X. View

Ritchie K, Artero S, Beluche I, Ancelin M, Mann A, Dupuy A . Prevalence of DSM-IV psychiatric disorder in the French elderly population. Br J Psychiatry. 2004; 184:147-52. DOI: 10.1192/bjp.184.2.147. View

Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin J, Humphries S . The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998; 102(7):1369-76. PMC: 508984. DOI: 10.1172/JCI2629. View

Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H . Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1998; 9(11):853-8. DOI: 10.1006/cyto.1997.0238. View

Huth C, Illig T, Herder C, Gieger C, Grallert H, Vollmert C . Joint analysis of individual participants' data from 17 studies on the association of the IL6 variant -174G>C with circulating glucose levels, interleukin-6 levels, and body mass index. Ann Med. 2008; 41(2):128-38. PMC: 3801210. DOI: 10.1080/07853890802337037. View

Krishnadas R, Cavanagh J . Depression: an inflammatory illness?. J Neurol Neurosurg Psychiatry. 2012; 83(5):495-502. DOI: 10.1136/jnnp-2011-301779. View

Baune B, Konrad C, Grotegerd D, Suslow T, Birosova E, Ohrmann P . Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain. J Neuroinflammation. 2012; 9:125. PMC: 3464888. DOI: 10.1186/1742-2094-9-125. View

Bocchio-Chiavetto L, Bagnardi V, Zanardini R, Molteni R, Gabriela Nielsen M, Placentino A . Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J Biol Psychiatry. 2010; 11(6):763-73. DOI: 10.3109/15622971003611319. View

10.

Dahl J, Ormstad H, Aass H, Malt U, Traskman Bendz L, Sandvik L . The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology. 2014; 45:77-86. DOI: 10.1016/j.psyneuen.2014.03.019. View

11.

Uddin M, Koenen K, Aiello A, Wildman D, de los Santos R, Galea S . Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. Psychol Med. 2010; 41(5):997-1007. PMC: 3065166. DOI: 10.1017/S0033291710001674. View

12.

Ehrich M, Nelson M, Stanssens P, Zabeau M, Liloglou T, Xinarianos G . Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci U S A. 2005; 102(44):15785-90. PMC: 1276092. DOI: 10.1073/pnas.0507816102. View

13.

Beekman A, Deeg D, van Limbeek J, Braam A, De Vries M, van Tilburg W . Criterion validity of the Center for Epidemiologic Studies Depression scale (CES-D): results from a community-based sample of older subjects in The Netherlands. Psychol Med. 1997; 27(1):231-5. DOI: 10.1017/s0033291796003510. View

14.

Roy B, Shelton R, Dwivedi Y . DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation. J Psychiatr Res. 2017; 89:115-124. PMC: 5391149. DOI: 10.1016/j.jpsychires.2017.02.005. View

15.

Maes M . Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010; 35(3):664-75. DOI: 10.1016/j.pnpbp.2010.06.014. View

16.

Zhang C, Wu Z, Zhao G, Wang F, Fang Y . Identification of IL6 as a susceptibility gene for major depressive disorder. Sci Rep. 2016; 6:31264. PMC: 4977523. DOI: 10.1038/srep31264. View

17.

Mansoori N, Tripathi M, Luthra K, Alam R, Lakshmy R, Sharma S . MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction. Neurobiol Aging. 2011; 33(5):1003.e1-8. DOI: 10.1016/j.neurobiolaging.2011.09.018. View

18.

Won E, Choi S, Kang J, Kim A, Han K, Chang H . Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder. Transl Psychiatry. 2016; 6(8):e866. PMC: 5022083. DOI: 10.1038/tp.2016.137. View

19.

Joyce B, Gao T, Liu L, Zheng Y, Liu S, Zhang W . Longitudinal Study of DNA Methylation of Inflammatory Genes and Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2015; 24(10):1531-8. PMC: 4592468. DOI: 10.1158/1055-9965.EPI-15-0198. View

20.

Na Y, Hong H, Lee W, Kim Y, Kim D . Increased methylation of interleukin 6 gene is associated with obesity in Korean women. Mol Cells. 2015; 38(5):452-6. PMC: 4443287. DOI: 10.14348/molcells.2015.0005. View