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. 2022 Jan 11;20(1):3.
doi: 10.1186/s12916-021-02193-0.

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

Emmanouil Bouras  1 , Ville Karhunen  2   3   4 , Dipender Gill  2   5   6   7 , Jian Huang  2   8 , Philip C Haycock  9   10 , Marc J Gunter  11 , Mattias Johansson  12 , Paul Brennan  12 , Tim Key  13 , Sarah J Lewis  9   14 , Richard M Martin  9   14   15 , Neil Murphy  11 , Elizabeth A Platz  16 , Ruth Travis  13 , James Yarmolinsky  9 , Verena Zuber  2 , Paul Martin  17 , Michail Katsoulis  18   19 , Heinz Freisling  11 , Therese Haugdahl Nøst  20   21 , Matthias B Schulze  22   23 , Laure Dossus  11 , Rayjean J Hung  24   25 , Christopher I Amos  26 , Ari Ahola-Olli  27   28   29 , Saranya Palaniswamy  2 , Minna Männikkö  30 , Juha Auvinen  3 , Karl-Heinz Herzig  31 , Sirkka Keinänen-Kiukaanniemi  3 , Terho Lehtimäki  32 , Veikko Salomaa  33 , Olli Raitakari  34   35 , Marko Salmi  36   37 , Sirpa Jalkanen  36   37 ; PRACTICAL consortium; Marjo-Riitta Jarvelin #  2   3   38 , Abbas Dehghan #  2   13   39 , Konstantinos K Tsilidis #  40   41
Collaborators, Affiliations

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

Emmanouil Bouras et al. BMC Med. .

Abstract

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.

Keywords: Cancer; Cytokines; Inflammation; Mendelian randomisation.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: DG is employed part-time by Novo Nordisk. VS has received honoraria from Novo Nordisk and Sanofi for consulting. He also has ongoing research collaboration with Bayer Ltd. (All unrelated to the present study). These companies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining authors have no competing interests to declare.

Figures

Fig. 1
Fig. 1
Overview of the analytical plan
Fig. 2
Fig. 2
Summary of the MR-IVW results based on the cis-pQTL instrument definition. Squared tiles indicate that the association is nominally significant (p < 0.05), and the asterisk denotes that the association was significant when considering multiple comparison correction (FDR ≤ 10%). Colour is scaled based on the MR beta estimates, while associations for which no instrument was available are presented as white tiles
Fig. 3
Fig. 3
Summary of the MR-IVW results based on the cis-eQTL instrument definition. Squared tiles indicate that the association is nominally significant (p < 0.05), and the asterisk denotes that the association was significant when considering multiple comparison correction (FDR ≤ 10%). Colour is scaled based on the MR beta estimates, while associations for which no instrument was available are presented as white tiles
Fig. 4
Fig. 4
Summary MR-IVW and sensitivity analyses of the associations that were significant when considering multiple comparison correction (FDR ≤ 10%)
See this image and copyright information in PMC

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