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Interleukin-6 and risk of colorectal cancer: results from the CLUE II cohort and a meta-analysis of prospective studies

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Abstract

Purpose

The association between prediagnostic interleukin-6 (IL-6) concentrations and risk of colorectal cancer was evaluated in a nested case–control study and a meta-analysis of prospective studies.

Methods

Colorectal cancer cases (n = 173) and matched controls (n = 345) were identified between 1989 and 2000 among participants in the CLUE II cohort of Washington Country, Maryland. Matched odds ratios and the corresponding 95 % confidence intervals (CIs) were estimated using conditional logistic regression models.

Results

Participants in the highest third of plasma IL-6 concentration had a 2.48 times higher risk of colon cancer compared to participants in the bottom third (95 % CI 1.26–4.87; p-trend 0.02) after multivariate adjustment. This association did not differ according to the stage of disease, age, sex, or other potential modifying variables and remained statistically significant after adjustment for C-reactive protein concentrations. No statistically significant association was observed for rectal cancer risk. The meta-analysis of six prospective studies yielded an increased but borderline statistically significant risk of colon cancer per 1 U increase in naturally logarithm-transformed IL-6 (summary RR 1.22; 95 % CI 1.00–1.49; I 2 46 %). An inverse association was noted for rectal cancer (RR 0.69; 95 % CI 0.54–0.88; I 2 0 %), but there was evidence for small-study effects (p 0.02).

Conclusion

Our findings provide support for a modest positive association between IL-6 concentrations and colon cancer risk. More work is needed to determine whether IL-6 is a valid marker of colorectal inflammation and whether such inflammation contributes to colon and rectal cancer risk.

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Acknowledgments

The authors thank Despoina Capothanassi for her statistical programming support, Dr. Thomas P Erlinger for his support of research on inflammation biomarkers and colorectal cancer risk in CLUE, and the authors of the original studies (Drs. Katriina Heikkila, Andrew Chan, Gloria Ho, and Mingyang Song), who kindly and promptly replied to our requests for additional information. Cancer incidence data were provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Department of Health and Mental Hygiene, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://phpa.dhmh.maryland.gov/cancer, 410-767-4055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, the Washington County Cancer Registry, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention (CDC) for the funds that helped support the availability of the cancer registry data. The findings and conclusions of this report are those of the authors and do not necessarily represent the views of the Department of Health and Mental Hygiene.

Funding

This research was funded by the American Institute for Cancer Research and the Maryland Cigarette Restitution Fund at Johns Hopkins, and the National Cancer Institute (P30 CA006973 to W.G. Nelson).

Author Contributions

JH-B, KJH, and EAP were involved in formulating the hypothesis and the design of the study protocol. The study hypothesis arose before inspection of the data. All authors had full access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. GB and NR measured the IL-6 concentrations. AK, CK, and KKT carried out the search of the literature, data abstraction, data management, and statistical analysis. DSL verified several inputs of the final database of the meta-analysis. AK, CK, EAP, and KKT wrote the first draft, and all authors contributed to further drafts and approved the final version submitted.

Author information

Authors and Affiliations

  1. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Stavros Niarchos Av., University Campus, Ioannina, Greece

    Artemisia Kakourou, Charalampia Koutsioumpa & Konstantinos K. Tsilidis

  2. Division of Epidemiology, University of Texas School of Public Health, Houston, TX, USA

    David S. Lopez

  3. Division of Urology, University of Texas Medical School, Houston, TX, USA

    David S. Lopez

  4. George W. Comstock Center for Public Health Research and Prevention, Johns Hopkins Bloomberg School of Public Health, Hagerstown, MD, USA

    Judith Hoffman-Bolton

  5. Department of Laboratory Medicine, Harvard Medical School and Children’s Hospital, Boston, MA, USA

    Gary Bradwin & Nader Rifai

  6. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Kathy J. Helzlsouer & Elizabeth A. Platz

  7. Department of Urology and James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Elizabeth A. Platz

  8. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    Elizabeth A. Platz

  9. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

    Konstantinos K. Tsilidis

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  1. Artemisia Kakourou
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Corresponding author

Correspondence to Konstantinos K. Tsilidis.

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Competing interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: [1] No authors have support from any company for the submitted work; [2] no authors have relationships with any company that might have an interest in the submitted work; [3] the authors’ spouses, partners, or children do not have any financial relationships that may be relevant to the submitted work; and [4] all authors have no nonfinancial interests that may be relevant to the submitted work.

Ethical approval

All participants provided informed consent, and the Institutional Review Board at the Johns Hopkins Bloomberg School of Public Health approved the study. The evidence synthesis study did not require an ethics approval.

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Kakourou, A., Koutsioumpa, C., Lopez, D.S. et al. Interleukin-6 and risk of colorectal cancer: results from the CLUE II cohort and a meta-analysis of prospective studies. Cancer Causes Control 26, 1449–1460 (2015). https://doi.org/10.1007/s10552-015-0641-1

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  • DOI: https://doi.org/10.1007/s10552-015-0641-1

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