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Title: Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses
Author: Khoei, Nazlisadat Seyed
Jenab, Mazda
Murphy, Neil
Banbury, Barbara L.
Carreras Torres, Robert
Viallon, Vivian
Kühn, Tilman
Bueno de Mesquita, H. 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 Bonet, Catalina
Rodríguez Barranco, Miguel
Gil, Leire
Chirlaque, María Dolores
Ardanaz, Eva
Myte, Robin
Hultdin, Johan
Pérez 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.
Cotterchio, Michelle
Gallinger, Steven
Gruber, Stephen B.
Haile, Robert W.
Hampe, Jochen
Hoffmeister, Michael
Hopper, John L.
Hsu, Li
Huyghe, Jeroen R.
Jenkins, Mark A.
Joshi, Amit D.
Kampman, Ellen
Larsson, Susanna C.
Marchand, Loïc Le
Li, Christopher I.
Li, Li
Lindblom, Annika
Lindor, Noralane M.
Martín Sánchez, Vicente
Moreno Aguado, Víctor
Newcomb, Polly A.
Offit, Kenneth
Ogino, Shuji
Parfrey, Patrick S.
Pharoah, Paul D. P.
Rennert, Gad
Sakoda, Lori C.
Schafmayer, Clemens
Schmit, Stephanie L.
Schoen, Robert E.
Slattery, Martha L.
Thibodeau, Stephen N.
Ulrich, Cornelia M.
van Duijnhoven, Franzel J. B.
Weigl, Korbinian
Weinstein, Stephanie J.
White, Emily
Wolk, Alicja
Woods, Michael O.
Wu, Anna H.
Zhang, Xuehong
Ferrari, Pietro
Anton, Gabriele
Peters, Annette
Peters, Ulrike
Gunter, Marc J.
Wagner, Karl-Heinz
Freisling, Heinz
Keywords: Càncer colorectal
Colorectal cancer
Issue Date: 3-Sep-2020
Publisher: BioMed Central
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 x 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 (P-heterogeneity = 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 mainUGT1A1SNP (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 (P-heterogeneity >= 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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It is part of: BMC Medicine, 2020, vol. 18
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Appears in Collections:Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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