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@ARTICLE{Bouka:310336,
      author       = {M. Bouka and K. Nimptsch and T. T. Pham and E. Bouras and
                      A. Kanellopoulou and A. I. Phipps and B. Van Guelpen and H.
                      Brenner$^*$ and L. Li and L. Le Marchand and K. K. Tsilidis
                      and T. Pischon},
      title        = {{A}ssociations of genetically predicted interleukin-6 and
                      tumor necrosis factor signaling pathways with mortality
                      among persons with colorectal cancer: a two-sample
                      {M}endelian randomization.},
      journal      = {BMC medicine},
      volume       = {nn},
      issn         = {1741-7015},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2026-00537},
      pages        = {nn},
      year         = {2026},
      note         = {#DKTKZFB26# / #NCTZFB26# / epub},
      abstract     = {Despite significant progress in identifying risk factors
                      for colorectal cancer (CRC), factors influencing survival in
                      people with CRC remain less understood. Pro-inflammatory
                      cytokines like interleukin-6 (IL-6) and tumor necrosis
                      factor-alpha (TNF-α) have been implicated in cancer
                      progression and may influence CRC outcomes. We investigated
                      associations between genetically predicted levels of IL-6
                      and TNF-α signaling pathways and mortality in people with
                      CRC.We conducted a two-sample Mendelian randomization (MR)
                      analysis using cis-acting single nucleotide polymorphisms
                      (SNPs) associated with soluble IL-6 receptor alpha (sIL6-RA)
                      and IL-6 signal transducer gp130 (IL6ST), representing IL-6
                      signaling, and with TNF-α, and its soluble receptors
                      (sTNF-R1, sTNF-R2). SNPs were obtained separately from two
                      large genome-wide association studies (GWAS): deCODE and UK
                      Biobank (UKB). The outcome was CRC-specific mortality among
                      16,964 CRC cases (4010 deaths) in the Genetics and
                      Epidemiology of Colorectal Cancer Consortium (GECCO).
                      Analyses were stratified by tumor site and stage. The
                      inverse variance weighted (IVW) method, incorporating a
                      correlation matrix for dependent SNPs, was used for primary
                      analyses. Because literature links TNF-α to CRC incidence,
                      we additionally performed a simulation study to evaluate the
                      potential impact of collider bias resulting from restricting
                      analyses to CRC cases.Genetically predicted sIL6-RA was
                      weakly positively associated with CRC-specific mortality
                      (deCODE-SNPs (n = 13) HR per 1 SD increase: 1.06; $95\%$ CI:
                      1.00-1.12; UKB-SNPs (n = 11) HR: 1.09; $95\%$ CI:
                      1.02-1.17). Genetically proxied IL6ST levels showed no
                      association with CRC-specific mortality in the overall
                      sample (deCODE-SNPs (n = 19) HR: 1.04; $95\%$ CI: 0.90-1.21;
                      UKB-SNPs (n = 9) HR: 1.11; $95\%$ CI: 0.87-2.42), while
                      higher IL6ST levels were associated with increased mortality
                      among patients with stage 2/3 disease (deCODE-SNPs (n = 19)
                      HR: 1.45; $95\%$ CI: 1.10-1.91; UKB-SNPs (n = 9) HR: 1.87;
                      $95\%$ CI: 1.22-2.89). No associations were observed for
                      TNF-α, sTNF-R1, or sTNF-R2. Findings for all exposures were
                      consistent across both GWAS datasets. Simulation analyses
                      for TNF-α indicated collider bias was present but limited
                      in magnitude.Our findings suggest that IL-6 signaling may
                      play a role in CRC progression although of limited
                      magnitude, whereas TNF-related pathways appear less relevant
                      for prognosis.},
      keywords     = {Colorectal cancer (Other) / IL-6 (Other) / Inflammation
                      (Other) / Mendelian randomization (Other) / Mortality
                      (Other) / TNF-α (Other)},
      cin          = {C070 / C120 / HD01 / HD02},
      ddc          = {610},
      cid          = {I:(DE-He78)C070-20160331 / I:(DE-He78)C120-20160331 /
                      I:(DE-He78)HD01-20160331 / I:(DE-He78)HD02-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41792766},
      doi          = {10.1186/s12916-026-04736-9},
      url          = {https://inrepo02.dkfz.de/record/310336},
}