Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

PRACTICAL Consortium, Emmanouil Bouras, Ville Karhunen, Dipender Gill, Jian Huang, Philip C Haycock, Marc J Gunter, Mattias Johansson, Paul Brennan, Tim Key, Sarah J Lewis, Richard M Martin, Neil Murphy, Elizabeth A Platz, Ruth Travis, James Yarmolinsky, Verena Zuber, Paul Martin, Michail Katsoulis, Heinz FreislingTherese Haugdahl Nøst, Matthias B Schulze, Laure Dossus, Rayjean J Hung, Christopher I Amos, Ari Ahola-Olli, Saranya Palaniswamy, Minna Männikkö, Juha Auvinen, Karl-Heinz Herzig, Sirkka Keinänen-Kiukaanniemi, Terho Lehtimäki, Veikko Salomaa, Olli Raitakari, Marko Salmi, Sirpa Jalkanen, Marjo-Riitta Jarvelin, Abbas Dehghan, Konstantinos K Tsilidis

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BACKGROUND: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis.

METHODS: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer).

RESULTS: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses.

CONCLUSIONS: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Original languageEnglish
Article number3
Number of pages15
JournalBmc Medicine
Publication statusPublished - 11 Jan 2022
Publication typeA1 Journal article-refereed


  • Cytokines/genetics
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mendelian Randomization Analysis
  • Ovarian Neoplasms/epidemiology
  • Polymorphism, Single Nucleotide
  • Risk Factors

Publication forum classification

  • Publication forum level 2


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  • Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

    Bouras, E. (Creator), Karhunen, V. (Creator), Gill, D. (Creator), Huang, J. (Creator), Haycock, P. C. (Creator), Gunter, M. J. (Creator), Johansson, M. (Creator), Brennan, P. (Creator), Key, T. (Creator), Lewis, S. J. (Creator), Martin, R. M. (Creator), Murphy, N. (Creator), Platz, E. A. (Creator), Travis, R. (Creator), Yarmolinsky, J. (Creator), Zuber, V. (Creator), Martin, P. (Creator), Katsoulis, M. (Creator), Freisling, H. (Creator), Nøst, T. H. (Creator), Schulze, M. B. (Creator), Dossus, L. (Creator), Hung, R. J. (Creator), Amos, C. I. (Creator), Ahola-Olli, A. (Creator), Palaniswamy, S. (Creator), Männikkö, M. (Creator), Auvinen, J. (Creator), Herzig, K.-H. (Creator), Keinänen-Kiukaanniemi, S. (Creator), Lehtimäki, T. (Creator), Salomaa, V. (Creator), Raitakari, O. (Creator), Salmi, M. (Creator), Jalkanen, S. (Creator), Jarvelin, M.-R. (Creator), Dehghan, A. (Creator) & Tsilidis, K. K. (Creator), 11 Jan 2022


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