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Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.
Seyed Khoei, Nazlisadat; Jenab, Mazda; Murphy, Neil; Banbury, Barbara L; Carreras-Torres, Robert; Viallon, Vivian; Kühn, Tilman; Bueno-de-Mesquita, Bas; Aleksandrova, Krasimira; Cross, Amanda J; Weiderpass, Elisabete; Stepien, Magdalena; Bulmer, Andrew; Tjønneland, Anne; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Carbonnel, Franck; Katzke, Verena; Boeing, Heiner; Bergmann, Manuela M; Trichopoulou, Antonia; Karakatsani, Anna; Martimianaki, Georgia; Palli, Domenico; Tagliabue, Giovanna; Panico, Salvatore; Tumino, Rosario; Sacerdote, Carlotta; Skeie, Guri; Merino, Susana; Bonet, Catalina; Rodríguez-Barranco, Miguel; Gil, Leire; Chirlaque, Maria-Dolores; Ardanaz, Eva; Myte, Robin; Hultdin, Johan; Perez-Cornago, Aurora; Aune, Dagfinn; Tsilidis, Konstantinos K; Albanes, Demetrius; Baron, John A; Berndt, Sonja I; Bézieau, Stéphane; Brenner, Hermann; Campbell, Peter T; Casey, Graham; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J.
Affiliation
  • Seyed Khoei N; Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
  • Jenab M; Nutritional Epidemiology Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • Murphy N; Nutritional Epidemiology Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • Banbury BL; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Carreras-Torres R; Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL). L'Hospitalet de Llobregat, Barcelona, Spain.
  • Viallon V; 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.
  • Kühn T; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Bueno-de-Mesquita B; Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
  • Aleksandrova K; Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands.
  • Cross AJ; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Weiderpass E; Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
  • Stepien M; Group Nutrition, Immunity and Metabolism, Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
  • Bulmer A; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Tjønneland A; International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • Boutron-Ruault MC; Nutritional Epidemiology Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • Severi G; School of Medicine, Griffith University, Brisbane, QLD, Australia.
  • Carbonnel F; Alliance for Vascular Access Teaching and Research (AVATAR), Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia.
  • Katzke V; Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Boeing H; Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
  • Bergmann MM; 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.
  • Trichopoulou A; Institut Gustave Roussy, Villejuif, France.
  • Karakatsani A; 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.
  • Martimianaki G; Institut Gustave Roussy, Villejuif, France.
  • Palli D; 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.
  • Tagliabue G; Institut Gustave Roussy, Villejuif, France.
  • Panico S; Department of Gastroenterology, Bicêtre University Hospital, Public Assistance Hospitals of Paris, Le Kremlin Bicêtre, France.
  • Tumino R; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Sacerdote C; Department of Epidemiology, German Institute of Human Nutrition Postdam-Rehbrücke, Nuthetal, Germany.
  • Skeie G; Department of Epidemiology, German Institute of Human Nutrition Postdam-Rehbrücke, Nuthetal, Germany.
  • Merino S; Hellenic Health Foundation, Athens, Greece.
  • Bonet C; Hellenic Health Foundation, Athens, Greece.
  • Rodríguez-Barranco M; 2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Haidari, Greece.
  • Gil L; Hellenic Health Foundation, Athens, Greece.
  • Chirlaque MD; Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
  • Ardanaz E; Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Myte R; Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
  • Hultdin J; Cancer Registry and Histopathology Department, "M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.
  • Perez-Cornago A; Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
  • Aune D; Department of Community Medicine, Faculty of Health Sciences, University of Tromsø (UiT), The Arctic University of Norway, Tromsø, Norway.
  • Tsilidis KK; Nutritional Epidemiology Group, School of Food and Nutrition, University of Leeds, Leeds, UK.
  • Albanes D; Public Health Directorate, Asturias, Spain.
  • Baron JA; Cancer Epidemiology Research Program, Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
  • Berndt SI; Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria, ibs. GRANADA, Universidad de Granada, Granada, Spain.
  • Bézieau S; CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
  • Brenner H; Public Health Division of Gipuzkoa-BIODONOSTIA, Basque Regional Health Department, San Sebastian, Spain.
  • Campbell PT; CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
  • Casey G; Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain.
  • Chan AT; CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
  • Chang-Claude J; Navarra Public Health Institute, Pamplona, Spain.
  • Chanock SJ; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
BMC Med ; 18(1): 229, 2020 09 03.
Article in En | MEDLINE | ID: mdl-32878631
ABSTRACT

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.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bilirubin / Colorectal Neoplasms / Mendelian Randomization Analysis Type of study: Clinical_trials / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: En Journal: BMC Med Journal subject: MEDICINA Year: 2020 Type: Article Affiliation country: Austria

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bilirubin / Colorectal Neoplasms / Mendelian Randomization Analysis Type of study: Clinical_trials / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: En Journal: BMC Med Journal subject: MEDICINA Year: 2020 Type: Article Affiliation country: Austria