University of Oulu

Bouras, E., Karhunen, V., Gill, D. et al. Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis. BMC Med 20, 3 (2022).

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

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Author: Bouras, Emmanouil1; Karhunen, Ville2,3,4; Gill, Dipender2,5,6,7;
Organizations: 1Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Ioannina, Greece.
2Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, St Marys Campus, London W2 1PG, England.
3Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland.
4Univ Oulu, Res Unit Math Sci, Oulu, Finland.
5Novo Nordisk Res Ctr Oxford, Old Rd Campus, Oxford, England.
6St Georges Univ Hosp NHS Fdn Trust, Clin Pharmacol Grp, Pharm & Med Directorate, London, England.
7St Georges Univ London, Inst Infect & Immun, Clin Pharmacol & Therapeut Sect, London, England.
8ASTAR, Singapore Inst Clin Sci SICS, Singapore, Singapore.
9Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
10Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England.
11WHO, Nutr & Metab Branch, Int Agcy Res Canc, Lyon, France.
12WHO, Genom Branch, Int Agcy Res Canc, Lyon, France.
13Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England.
14Univ Bristol, Bristol Med Sch, Dept Populat Hlth Sci, Bristol, Avon, England.
15Univ Hosp Bristol NHS Fdn Trust, Natl Inst Hlth Res NIHR, Bristol Biomed Res Ctr, Bristol, Avon, England.
16Univ Bristol, Bristol, Avon, England.
17Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.
18Univ Bristol, Sch Biochem, Bristol, Avon, England.
19UCL, Inst Hlth Informat, London, England.
20Hlth Data Res UK, London, England.
21Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, Tromso, Norway.
22Norwegian Univ Sci & Technol, KG Jebsen Ctr Genet Epidemiol, Dept Publ Hlth & Nursing, Trondheim, Norway.
23German Inst Human Nutr Potsdam Rehbrucke, Dept Mol Epidemiol, Nutehtal, Germany.
24Univ Potsdam, Inst Nutr Sci, Potsdam, Germany.
25Lunenfeld Tanenbaum Res Inst Sinai Hlth Syst, Prosserman Ctr Populat Hlth Res, Toronto, ON, Canada.
26Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada.
27Baylor Coll Med, Houston, TX 77030 USA.
28Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.
29Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
30Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.
31Univ Oulu, Fac Med, Infrastruct Populat Studies, Northern Finland Birth Cohorts, Oulu, Finland.
32Univ Oulu, Res Unit Biomed, Fac Med, Med Res Ctr, Oulu, Finland.
33Oulu Univ Hosp, Oulu, Finland.
34Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Chem, Tampere, Finland.
35Finnish Inst Hlth & Welf, Helsinki, Finland.
36Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
37Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.
38Univ Turku, Med Res Lab, Turku, Finland.
39Univ Turku, Inst Biomed, Turku, Finland.
40Oulu Univ Hosp, Unit Primary Care, Oulu, Finland.
41Imperial Coll London, UK Dementia Res Inst, London, England.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.7 MB)
Persistent link:
Language: English
Published: Springer Nature, 2022
Publish Date: 2022-08-22


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.

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Series: BMC medicine
ISSN: 1741-7015
ISSN-E: 1741-7015
ISSN-L: 1741-7015
Volume: 20
Issue: 1
Article number: 3
DOI: 10.1186/s12916-021-02193-0
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
3111 Biomedicine
Funding: This work was supported by a Cancer Research UK Programme Grant of Research Excellence (RE/18/4/34215) at Imperial College and a National Institute for Health Research Clinical Lectureship funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant 721567 (CAPICE project) and grant 848158 (EarlyCause), and the Academy of Finland [Project 312123]. This project has received funding from the European Union's Horizon 2020 research and innovation programme (666881), SVDs@target (to MD; 667375), CoSTREAM (to MD); the DFG as part of the Munich Cluster for Systems Neurology (SyNergy, EXC EXC 2145 SyNergy -ID 390857198), the CRC 1123 (B3; to MD) and project DI 722/13-1; the Corona Foundation (to MD); the LMUexcellent fond (to MD); the e:Med program (e:AtheroSysMed; to MD) and the FP7/20072103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456; to MD). NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. SJL and RMM were supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. JY is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C68933/A28534). TK and RT were supported by Cancer Research UK (grants C8221/A29017) and the Medical Research Council (grant MR/M012190/1). CIA and RH are supported by U19CA203654. CIA is a Research Scholar of the Cancer Prevention Research Institute of Texas and supported by CPRIT RR170048. VS was supported by the Finnish Foundation for Cardiovascular Research. SJ and MS were supported by the Finnish Academy. PCH was supported by Cancer Research UK (C52724/A20138 numbers 24300796, 24302031, 285547 (EGEA); the Medical Research Council and Biological Sciences Research Council PREcisE (Nutrition & Epigenome, The Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL/EU-H2020)); SP and MRJ are supported by the European Union's Horizon 2020 programme EDCMET (grant number 825762). Funding sources of the PRACTICAL, CRUK, BPC3, CAPS and PEGASUS consortia are described in the Additional file 1.
EU Grant Number: (825762) EDCMET - Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways
(848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity
Academy of Finland Grant Number: 312123
Detailed Information: 312123 (Academy of Finland Funding decision)
285547 (Academy of Finland Funding decision)
Dataset Reference: The online version contains supplementary material available at https://doi. org/10.1186/s12916-021-02193-0.
  https://doi. org/10.1186/s12916-021-02193-0
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