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Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case\u2013control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (<jats:italic>n<\/jats:italic>\u2009=\u200959 with CRP &lt;1, <jats:italic>n<\/jats:italic>\u2009=\u200933 with CRP 1\u20133 and <jats:italic>n<\/jats:italic>\u2009=\u200936 with CRP &gt;3\u2009mg\/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12\/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP &gt;3 vs. CRP &lt;1 and\/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values &lt;1\u2009mg\/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.<\/jats:p>","DOI":"10.1038\/s41398-023-02438-x","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T14:02:21Z","timestamp":1685628141000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP 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Prof. Pariante have received research funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2, as part of the EU-PEARL project. This Joint Undertaking receives support from the European Union\u2019s Horizon 2020 research and innovation programme and EFPIA. Prof. Pariante is also funded by a Senior Investigator award from the National Institute for Health Research (NIHR); the Medical Research Council (grants MR\/L014815\/1, MR\/J002739\/1 and MR\/N029488\/1); the European Commission (EARLYCAUSE grant SC1-BHC-01-2019); the NARSAD; the Psychiatry Research Trust; and the Wellcome Trust (SHAPER, Scaling-up Health-Arts Programme to scale up arts interventions, grant 219425\/Z\/19\/Z). Less than 10% of his support in the last 10 years derives from commercial collaborations, including consultation and speakers fees from Boehringer Ingelheim, Eli Lilly, Compass, Eleusis, GH Research, Lundbeck, and V\u00e4rde Partners. Dr Mondelli is also funded by MQ: Transforming Mental Health (Grant: MQBF\/1 and MQBF\/4) and the Medical Research Foundation (Grant: MRF-160-0005-ELP-MONDE).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"185"}}