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Inflammopharmacology

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06-05-2023 | Affective Disorder | Original Article

The role of inflammatory biomarkers in the association between rheumatoid arthritis and depression: a Mendelian randomization study

Authors: Shate Xiang, Danyi Xu, Yibo Jin, Rongyun Wang, Chengping Wen, Xinghong Ding

Published in: Inflammopharmacology | Issue 4/2023

Abstract

Background

Inflammation may mediate the co-pathogenesis of rheumatoid arthritis (RA) and depression because inflammatory cytokines are associated with RA and depression. However, traditional observational research was not able to address problems with residual confusion and reverse causality.

Methods

We summarized and retrieved 28 inflammatory cytokines associated with RA, depression, or RA with depression through a literature search. The summary statistics from genome-wide association studies for RA, inflammatory biomarkers, broad depression, and major depression disease phenotypes were used. Mendelian randomization was performed to assess the causal association between RA and inflammatory biomarkers, as well as the effects of inflammatory biomarkers on depression. Bonferroni correction was used to reduce the possibility of false positive results.

Results

The study found that evidence for associations of genetically predicted RA was associated with higher levels of interleukin (IL)-9 (OR = 1.035, 95%CI = 1.002–1.068, P = 0.027), IL-12 (OR = 1.045, 95%CI = 1.045–1.014, P = 0.004), IL-13 (OR = 1.060, 95%CI = 1.028–1.092, P = 0.0001), IL-20 (OR = 1.037, 95%CI = 1.001–1.074, P = 0.047), and IL-27 (OR = 1.017, 95%CI = 1.003–1.032, P = 0.021). The level of IL-7 (OR = 1.029, 95%CI = 1.018–1.436, P = 0.030) was significantly related to RA. Only the analysis results between RA and IL-13 were satisfied with the statistical significance threshold corrected by Bonferroni (P < 0.002). However, a causal effect was not found between inflammatory biomarkers and depression.

Conclusions

In the current study the inflammatory cytokines associated with RA comorbid depression may not be the mediators that directly lead to the co-pathogenesis of RA and depression.

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Ahola-Olli AV, Würtz P, Havulinna AS, Aalto K, Pitkänen N, Lehtimäki T, Kähönen M, Lyytikäinen LP, Raitoharju E, Seppälä I, Sarin AP, Ripatti S, Palotie A, Perola M, Viikari JS, Jalkanen S, Maksimow M, Salomaa V, Salmi M, Kettunen J, Raitakari OT (2017) Genome-wide association study identifies 27 loci influencing concentrations of circulating cytokines and growth factors. Am J Hum Genet 100:40–50. https://doi.org/10.1016/j.ajhg.2016.11.007CrossRefPubMed

Amaral AFS, Imboden M, Wielscher M, Rezwan FI, Minelli C, Garcia-Aymerich J, Peralta GP, Auvinen J, Jeong A, Schaffner E, Beckmeyer-Borowko A, Holloway JW, Jarvelin MR, Probst-Hensch NM, Jarvis DL (2020) Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study. BMC Pulm Med 20:171. https://doi.org/10.1186/s12890-020-01212-9CrossRefPubMedPubMedCentral

Azizieh FY, Al Jarallah K, Shehab D, Gupta R, Dingle K, Raghupathy R (2017) Patterns of circulatory and peripheral blood mononuclear cytokines in rheumatoid arthritis. Rheumatol Int 37:1727–1734. https://doi.org/10.1007/s00296-017-3774-6CrossRefPubMed

Barra L, Summers K, Bell D, Cairns E (2014) Serum cytokine profile of unaffected first-degree relatives of patients with rheumatoid arthritis. J Rheumatol 41:280–285. https://doi.org/10.3899/jrheum.130539CrossRefPubMed

Belleau EL, Treadway MT, Pizzagalli DA (2019) The impact of stress and major depressive disorder on hippocampal and medial prefrontal cortex morphology. Biol Psychiat 85:443–453. https://doi.org/10.1016/j.biopsych.2018.09.031CrossRefPubMed

Beurel E, Toups M, Nemeroff CB (2020) The bidirectional relationship of depression and inflammation: double trouble. Neuron 107:234–256. https://doi.org/10.1016/j.neuron.2020.06.002CrossRefPubMedPubMedCentral

Bowden J, Davey Smith G, Haycock PC, Burgess S (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 40:304–314. https://doi.org/10.1002/gepi.21965CrossRefPubMedPubMedCentral

Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32:377–389. https://doi.org/10.1007/s10654-017-0255-xCrossRefPubMedPubMedCentral

Carter AR, Sanderson E, Hammerton G, Richmond RC, Davey Smith G, Heron J, Taylor AE, Davies NM, Howe LD (2021) Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol 36:465–478. https://doi.org/10.1007/s10654-021-00757-1CrossRefPubMedPubMedCentral

Chen Z, Bozec A, Ramming A, Schett G (2019) Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol 15:9–17. https://doi.org/10.1038/s41584-018-0109-2CrossRefPubMed

Cheon YH, Lee SG, Kim M, Kim HO, Sun Suh Y, Park KS, Kim RB, Yang HS, Kim JM, Son CN, Kyoung Park E, Kim SH, Lee SI (2018) The association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression in patients with rheumatoid arthritis. Brain Behav Immun 73:274–281. https://doi.org/10.1016/j.bbi.2018.05.012CrossRefPubMed

Choy EHS, Calabrese LH (2018) Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (oxford) 57:1885–1895. https://doi.org/10.1093/rheumatology/kex391CrossRefPubMed

Cordingley L, Prajapati R, Plant D, Maskell D, Morgan C, Ali FR, Morgan AW, Wilson AG, Isaacs JD, Barton A (2014) Impact of psychological factors on subjective disease activity assessments in patients with severe rheumatoid arthritis. Arthritis Care Res 66:861–868. https://doi.org/10.1002/acr.22249CrossRef

Cornish AJ, Law PJ, Timofeeva M, Palin K, Farrington SM, Palles C, Jenkins MA, Casey G, Brenner H, Chang-Claude J, Hoffmeister M, Kirac I, Maughan T, Brezina S, Gsur A, Cheadle JP, Aaltonen LA, Tomlinson I, Dunlop MG, Houlston RS (2020) Modifiable pathways for colorectal cancer: a Mendelian randomisation analysis. Lancet Gastroenterol Hepatol 5:55–62. https://doi.org/10.1016/s2468-1253(19)30294-8CrossRefPubMed

de Oliveira P, Ribeiro N, de Mello R, Schier A, Ornelas AC, Pinho de Oliveira CM, Nardi AE, Silva AC (2013) Anxiety, depression and suicidal ideation in patients with rheumatoid arthritis in use of methotrexate, hydroxychloroquine, leflunomide and biological drugs. Compr Psychiatry 54:1185–1189. https://doi.org/10.1016/j.comppsych.2013.05.010CrossRef

Eyre HA, Air T, Proctor S, Rositano S, Baune BT (2015) A critical review of the efficacy of non-steroidal anti-inflammatory drugs in depression. Prog Neuropsychopharmacol Biol Psychiatry 57:11–16. https://doi.org/10.1016/j.pnpbp.2014.10.003CrossRefPubMed

Fakra E, Marotte H (2021) Rheumatoid arthritis and depression. Joint Bone Spine 88:105200. https://doi.org/10.1016/j.jbspin.2021.105200CrossRefPubMed

Folkersen L, Gustafsson S, Wang Q, Hansen DH, Hedman ÅK, Schork A, Page K, Zhernakova DV, Wu Y, Peters J, Eriksson N, Bergen SE, Boutin TS, Bretherick AD, Enroth S, Kalnapenkis A, Gådin JR, Suur BE, Chen Y, Matic L, Gale JD, Lee J, Zhang W, Quazi A, Ala-Korpela M, Choi SH, Claringbould A, Danesh J, Davey Smith G, de Masi F, Elmståhl S, Engström G, Fauman E, Fernandez C, Franke L, Franks PW, Giedraitis V, Haley C, Hamsten A, Ingason A, Johansson Å, Joshi PK, Lind L, Lindgren CM, Lubitz S, Palmer T, Macdonald-Dunlop E, Magnusson M, Melander O, Michaelsson K, Morris AP, Mägi R, Nagle MW, Nilsson PM, Nilsson J, Orho-Melander M, Polasek O, Prins B, Pålsson E, Qi T, Sjögren M, Sundström J, Surendran P, Võsa U, Werge T, Wernersson R, Westra HJ, Yang J, Zhernakova A, Ärnlöv J, Fu J, Smith JG, Esko T, Hayward C, Gyllensten U, Landen M, Siegbahn A, Wilson JF, Wallentin L, Butterworth AS, Holmes MV, Ingelsson E, Mälarstig A (2020) Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nat Metab 2:1135–1148. https://doi.org/10.1038/s42255-020-00287-2CrossRefPubMedPubMedCentral

Gao C, Zhong H, Chen L, Wang L, Yao H, Huang X, Jia Y, Li C, Liu T (2022) Clinical and psychological assessment of patients with rheumatoid arthritis and fibromyalgia: a real-world study. Clin Rheumatol 41:1235–1240. https://doi.org/10.1007/s10067-021-06026-6CrossRefPubMed

Gwinnutt JM, Norton S, Hyrich KL, Lunt M, Combe B, Rincheval N, Ruyssen-Witrand A, Fautrel B, McWilliams DF, Walsh DA, Nikiphorou E, Kiely PDW, Young A, Chipping JR, MacGregor A, Verstappen SMM (2022) Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis. Rheumatology (oxford) 61:4687–4701. https://doi.org/10.1093/rheumatology/keac137CrossRefPubMed

Hare DL, Toukhsati SR, Johansson P, Jaarsma T (2014) Depression and cardiovascular disease: a clinical review. Eur Heart J 35:1365–1372. https://doi.org/10.1093/eurheartj/eht462CrossRefPubMed

Howard DM, Adams MJ, Shirali M, Clarke TK, Marioni RE, Davies G, Coleman JRI, Alloza C, Shen X, Barbu MC, Wigmore EM, Gibson J, Hagenaars SP, Lewis CM, Ward J, Smith DJ, Sullivan PF, Haley CS, Breen G, Deary IJ, McIntosh AM (2018) Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nat Commun 9:1470. https://doi.org/10.1038/s41467-018-03819-3CrossRefPubMedPubMedCentral

Howard DM, Adams MJ, Clarke TK, Hafferty JD, Gibson J, Shirali M, Coleman JRI, Hagenaars SP, Ward J, Wigmore EM, Alloza C, Shen X, Barbu MC, Xu EY, Whalley HC, Marioni RE, Porteous DJ, Davies G, Deary IJ, Hemani G, Berger K, Teismann H, Rawal R, Arolt V, Baune BT, Dannlowski U, Domschke K, Tian C, Hinds DA, Trzaskowski M, Byrne EM, Ripke S, Smith DJ, Sullivan PF, Wray NR, Breen G, Lewis CM, McIntosh AM (2019) Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci 22:343–352. https://doi.org/10.1038/s41593-018-0326-7CrossRefPubMedPubMedCentral

Hussein MS, El-Barbary AM, Nada DW, Gaber RA, Elkolaly RM, Aboelhawa MA (2021) Identification of serum interleukin-13 and interleukin-13 receptor subunit expressions: rheumatoid arthritis-associated interstitial lung disease. Int J Rheum Dis 24:591–598. https://doi.org/10.1111/1756-185x.14084CrossRefPubMed

Iwaszko M, Biały S, Bogunia-Kubik K (2021) Significance of interleukin (IL)-4 and IL-13 in inflammatory arthritis. Cells 10:3000. https://doi.org/10.3390/cells10113000CrossRefPubMedPubMedCentral

Judea P (2009) Causal inference in statistics: an overview. Stat Surv 3:96–146. https://doi.org/10.1214/09-SS057CrossRef

Kaufman JS (2019) Commentary: causal inference for social exposures. Annu Rev Public Health 40:7–21. https://doi.org/10.1146/annurev-publhealth-040218-043735CrossRefPubMed

Köhler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, Stubbs B, Solmi M, Veronese N, Herrmann N, Raison CL, Miller BJ, Lanctôt KL, Carvalho AF (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand 135:373–387. https://doi.org/10.1111/acps.12698CrossRefPubMed

Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G (2008) Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 27:1133–1163. https://doi.org/10.1002/sim.3034CrossRefPubMed

Lee YC, Frits ML, Iannaccone CK, Weinblatt ME, Shadick NA, Williams DA, Cui J (2014) Subgrouping of patients with rheumatoid arthritis based on pain, fatigue, inflammation, and psychosocial factors. Arthritis Rheumatol 66:2006–2014. https://doi.org/10.1002/art.38682CrossRefPubMedPubMedCentral

Luo J, Xu Z, Noordam R, van Heemst D, Li-Gao R (2022) Depression and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study. J Crohns Colitis 16:633–642. https://doi.org/10.1093/ecco-jcc/jjab191CrossRefPubMed

Mao L, Ren X, Wang X, Tian F (2022) Associations between autoimmunity and depression: serum IL-6 and IL-17 have directly impact on the HAMD scores in patients with first-episode depressive disorder. J Immunol Res 2022:6724881. https://doi.org/10.1155/2022/6724881CrossRefPubMedPubMedCentral

Matcham F, Rayner L, Steer S, Hotopf M (2013) The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (oxford) 52:2136–2148. https://doi.org/10.1093/rheumatology/ket169CrossRefPubMed

Morf H, da Rocha C-P, Vargas-Santos AB, Baerwald C, Seifert O (2021) Impact of clinical and psychological factors associated with depression in patients with rheumatoid arthritis: comparative study between Germany and Brazil. Clin Rheumatol 40:1779–1787. https://doi.org/10.1007/s10067-020-05470-0CrossRefPubMed

Nerurkar L, Siebert S, McInnes IB, Cavanagh J (2019) Rheumatoid arthritis and depression: an inflammatory perspective. The Lancet Psychiatry 6:164–173. https://doi.org/10.1016/s2215-0366(18)30255-4CrossRefPubMed

Nolde M, Holtfreter B, Kocher T, Alayash Z, Reckelkamm SL, Ehmke B, Baurecht H, Baumeister SE (2022) No bidirectional relationship between depression and periodontitis: a genetic correlation and Mendelian randomization study. Front Immunol 13:918404. https://doi.org/10.3389/fimmu.2022.918404CrossRefPubMedPubMedCentral

Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD, Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T, Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA, Diogo D, Cui J, Liao K, Guo MH, Myouzen K, Kawaguchi T, Coenen MJ, van Riel PL, van de Laar MA, Guchelaar HJ, Huizinga TW, Dieudé P, Mariette X, Bridges SL Jr, Zhernakova A, Toes RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS, Martin J, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Rantapää-Dahlqvist S, Arlestig L, Choi HK, Kamatani Y, Galan P, Lathrop M, Eyre S, Bowes J, Barton A, de Vries N, Moreland LW, Criswell LA, Karlson EW, Taniguchi A, Yamada R, Kubo M, Liu JS, Bae SC, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Raychaudhuri S, Stranger BE, De Jager PL, Franke L, Visscher PM, Brown MA, Yamanaka H, Mimori T, Takahashi A, Xu H, Behrens TW, Siminovitch KA, Momohara S, Matsuda F, Yamamoto K, Plenge RM (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506:376–381. https://doi.org/10.1038/nature12873CrossRefPubMed

Palmos AB, Hübel C, Lim KX, Hunjan AK, Coleman JRI, Breen G (2023) Assessing the evidence for causal associations between body mass index, c-reactive protein, depression, and reported trauma using Mendelian randomization. Biol Psychiatry Global Open Sci 3:110–118. https://doi.org/10.1016/j.bpsgos.2022.01.003CrossRef

Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF (2008) A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 23:183–189. https://doi.org/10.1002/mds.21803CrossRefPubMed

Sang N, Gao RC, Zhang MY, Wu ZZ, Wu ZG, Wu GC (2022) Causal relationship between sleep traits and risk of systemic lupus erythematosus: a two-sample Mendelian randomization study. Front Immunol 13:918749. https://doi.org/10.3389/fimmu.2022.918749CrossRefPubMedPubMedCentral

Shi X, Wei T, Hu Y, Wang M, Tang Y (2022) The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study. J Neuroinflammation 19:218. https://doi.org/10.1186/s12974-022-02582-zCrossRefPubMedPubMedCentral

Singh G, Mahajan N, Abrol S, Raina A (2021) Anxiety and depression are common in rheumatoid arthritis and correlate with poor quality of life in Indian patients. Reumatologia 59:386–393. https://doi.org/10.5114/reum.2021.112351CrossRefPubMedPubMedCentral

Smith GD, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32:1–22. https://doi.org/10.1093/ije/dyg070CrossRefPubMed

Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, Burgess S, Jiang T, Paige E, Surendran P, Oliver-Williams C, Kamat MA, Prins BP, Wilcox SK, Zimmerman ES, Chi A, Bansal N, Spain SL, Wood AM, Morrell NW, Bradley JR, Janjic N, Roberts DJ, Ouwehand WH, Todd JA, Soranzo N, Suhre K, Paul DS, Fox CS, Plenge RM, Danesh J, Runz H, Butterworth AS (2018) Genomic atlas of the human plasma proteome. Nature 558:73–79. https://doi.org/10.1038/s41586-018-0175-2CrossRefPubMedPubMedCentral

Takei S, Hoshino T, Matsunaga K, Sakazaki Y, Sawada M, Oda H, Takenaka S, Imaoka H, Kinoshita T, Honda S, Ida H, Fukuda TA, Aizawa H (2011) Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis. Arthritis Res Ther 13:R52. https://doi.org/10.1186/ar3295CrossRefPubMedPubMedCentral

Verbanck M, Chen CY, Neale B, Do R (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 50:693–698. https://doi.org/10.1038/s41588-018-0099-7CrossRefPubMedPubMedCentral

Waraich P, Goldner EM, Somers JM, Hsu L (2004) Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can J Psychiatry Revue Canadienne De Psychiatrie 49:124–138. https://doi.org/10.1177/070674370404900208CrossRefPubMed

Xiang S, Wang R, Hua L, Song J, Qian S, Jin Y, Zhang B, Ding X (2023) Assessment of bidirectional relationships between mental illness and rheumatoid arthritis: a two-sample Mendelian randomization study. J Clin Med 12:944. https://doi.org/10.3390/jcm12030944CrossRefPubMedPubMedCentral

Yuan S, Li X, Lin A, Larsson SC (2022) Interleukins and rheumatoid arthritis: bi-directional Mendelian randomization investigation. Semin Arthritis Rheum 53:151958. https://doi.org/10.1007/s10654-017-0255-xCrossRefPubMed

Ziyadeh NJ, Geldhof A, Noël W, Otero-Lobato M, Esslinger S, Chakravarty SD, Wang Y, Seeger JD (2020) Post-approval safety surveillance study of golimumab in the treatment of rheumatic disease using a United States healthcare claims database. Clin Drug Investig 40:1021–1040. https://doi.org/10.1007/s40261-020-00959-7CrossRefPubMedPubMedCentral

Title: The role of inflammatory biomarkers in the association between rheumatoid arthritis and depression: a Mendelian randomization study
Authors: Shate Xiang
Danyi Xu
Yibo Jin
Rongyun Wang
Chengping Wen
Xinghong Ding
Publication date: 06-05-2023
Publisher: Springer International Publishing
Keywords: Affective Disorder
Affective Disorder
Rheumatoid Arthritis
Biomarkers
Published in: Inflammopharmacology / Issue 4/2023
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-023-01241-w

At a glance: The STEP trials

Springer Medicine

The role of inflammatory biomarkers in the association between rheumatoid arthritis and depression: a Mendelian randomization study

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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