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Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.
Pubmed ID
32878631 (View this publication on the PubMed website)
Digital Object Identifier
BMC Med. 2020 Sep 3; Volume 18 (Issue 1): Pages 229
Seyed Khoei N, Jenab M, Murphy N, Banbury BL, Carreras-Torres R, Viallon V, Kühn T, Bueno-de-Mesquita B, Aleksandrova K, Cross AJ, Weiderpass E, Stepien M, Bulmer A, Tjønneland A, Boutron-Ruault MC, Severi G, Carbonnel F, Katzke V, Boeing H, Bergmann MM, more Trichopoulou A, Karakatsani A, Martimianaki G, Palli D, Tagliabue G, Panico S, Tumino R, Sacerdote C, Skeie G, Merino S, Bonet C, Rodríguez-Barranco M, Gil L, Chirlaque MD, Ardanaz E, Myte R, Hultdin J, Perez-Cornago A, Aune D, Tsilidis KK, Albanes D, Baron JA, Berndt SI, Bézieau S, Brenner H, Campbell PT, Casey G, Chan AT, Chang-Claude J, Chanock SJ, Cotterchio M, Gallinger S, Gruber SB, Haile RW, Hampe J, Hoffmeister M, Hopper JL, Hsu L, Huyghe JR, Jenkins MA, Joshi AD, Kampman E, Larsson SC, Le Marchand L, Li CI, Li L, Lindblom A, Lindor NM, Martín V, Moreno V, Newcomb PA, Offit K, Ogino S, Parfrey PS, Pharoah PDP, Rennert G, Sakoda LC, Schafmayer C, Schmit SL, Schoen RE, Slattery ML, Thibodeau SN, Ulrich CM, van Duijnhoven FJB, Weigl K, Weinstein SJ, White E, Wolk A, Woods MO, Wu AH, Zhang X, Ferrari P, Anton G, Peters A, Peters U, Gunter MJ, Wagner KH, Freisling H
  • Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
  • Nutritional Epidemiology Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL). L'Hospitalet de Llobregat, Barcelona, Spain.
  • Nutritional Methodology and Biostatistics Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69372, Lyon CEDEX 08, France.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
  • Group Nutrition, Immunity and Metabolism, Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • International Agency for Research on Cancer (IARC-WHO), Lyon, France. more
  • School of Medicine, Griffith University, Brisbane, QLD, Australia.
  • Danish Cancer Society Research Center, Copenhagen, Denmark.
  • CESP (Centre de Recherche en Epidémiologie et Santé des Populations), Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
  • Department of Epidemiology, German Institute of Human Nutrition Postdam-Rehbrücke, Nuthetal, Germany.
  • Hellenic Health Foundation, Athens, Greece.
  • Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
  • Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
  • Cancer Registry and Histopathology Department, "M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.
  • Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
  • Department of Community Medicine, Faculty of Health Sciences, University of Tromsø (UiT), The Arctic University of Norway, Tromsø, Norway.
  • Public Health Directorate, Asturias, Spain.
  • Cancer Epidemiology Research Program, Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
  • Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria, ibs. GRANADA, Universidad de Granada, Granada, Spain.
  • Public Health Division of Gipuzkoa-BIODONOSTIA, Basque Regional Health Department, San Sebastian, Spain.
  • CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
  • Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Division of Human Nutrition, Wageningen University and Research, Wageningen, The Netherlands.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA.
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • The Clinical Epidemiology Unit, Memorial University Medical School, Newfoundland, Canada.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • Department of General, Visceral, Vascular, and Transplantation Surgery, University Hospital Rostock, Rostock, Germany.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
  • Discipline of Genetics, Memorial University of Newfoundland, St. John's, Canada.
  • University of Southern California, Preventative Medicine, Los Angeles, CA, USA.
  • Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Institute of Epidemiology, Helmholtz Zentrum Munich, Neuherberg, Germany.
  • Nutritional Methodology and Biostatistics Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69372, Lyon CEDEX 08, France.

BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.

METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.

RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).

CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

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