title: The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.
abstract: BACKGROUND
  Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms.
  
  
  OBJECTIVE
  We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC).
  
  
  METHODS
  We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination.
  
  
  RESULTS
  The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively.
  
  
  CONCLUSIONS
  These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; krasimira.aleksandrova@dife.de.
authors.forename: Krasimira
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authors.lastname: Aleksandrova
authors.affiliation: WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece; Hellenic Health Foundation, Athens, Greece;
authors.forename: Christina
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authors.lastname: Bamia
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany;
authors.forename: Dagmar
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authors.lastname: Drogan
authors.affiliation: WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece; Department of Epidemiology, Harvard School of Public Health, Boston, MA; Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece;
authors.forename: Pagona
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authors.affiliation: WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece; Hellenic Health Foundation, Athens, Greece;
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authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA; Winship Cancer Institute, Emory University, Atlanta, GA;
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authors.lastname: Fedirko
authors.affiliation: International Agency for Research on Cancer, Lyon, France;
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authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, Netherlands; Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia;
authors.forename: H Bas
authors.initials: HB
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authors.affiliation: Molecular Epidemiology Group, Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany;
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authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, University Campus, Ioannina, Greece;
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authors.affiliation: Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark;
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authors.affiliation: Inserm, Centre for Research in Epidemiology and Population Health, Nutrition, Hormones and Women's Health Team, Villejuif, France; University Paris Sud, Villejuif, France; IGR, Villejuif, France;
authors.forename: Marie-Christine
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authors.affiliation: Inserm, Centre for Research in Epidemiology and Population Health, Nutrition, Hormones and Women's Health Team, Villejuif, France; University Paris Sud, Villejuif, France; IGR, Villejuif, France;
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authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany;
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authors.affiliation: Department of Clinical and Experimental Medicine-Federico II University, Naples, Italy;
authors.forename: Salvatore
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authors.affiliation: Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; HuGeF Foundation, Turin, Italy;
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authors.initials: PH
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authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway; Department of Research, Cancer Registry of Norway, Oslo, Norway; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland;
authors.forename: Elisabete
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authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway;
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authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway;
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authors.forename: María-José
authors.initials: MJ
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authors.initials: MD
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authors.affiliation: Department of Clinical Sciences, Lund University, Clinical Research Center, Malmö, Sweden;
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authors.affiliation: Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom;
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authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany;
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authors.affiliation: Hellenic Health Foundation, Athens, Greece; Department of Epidemiology, Harvard School of Public Health, Boston, MA; Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece;
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mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D016022:Case-Control Studies; D003069:Coffee / Q000009:adverse effects; D015331:Cohort Studies; D004032:Diet / Q000009:adverse effects; D005060:Europe / Q000453:epidemiology; D005260:Female; D006505:Hepatitis / Q000097:blood / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D015994:Incidence; D008099:Liver / Q000276:immunology*; D008113:Liver Neoplasms / Q000097:blood / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D013223:Statistics as Topic
chemical_list: D015415:Biomarkers; D003069:Coffee
keywords: European Prospective Investigation into Cancer and Nutrition; biomarkers; coffee; liver cancer; mediation