Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses
Creators: name: Seyed Khoei, Nazlisadat
name: Jenab, Mazda
name: Murphy, Neil
name: Banbury, Barbara L.
name: Carreras-Torres, Robert
name: Viallon, Vivian
name: Kühn, Tilman
name: Bueno-De-Mesquita, Bas
name: Aleksandrova, Krasimira
name: Cross, Amanda J.
name: Weiderpass, Elisabete
name: Stepien, Magdalena
name: Bulmer, Andrew
name: Tjønneland, Anne
name: Boutron-Ruault, Marie-Christine
name: Severi, Gianluca
name: Carbonnel, Franck
name: Katzke, Verena
name: Boeing, Heiner
name: Bergmann, Manuela M.
name: Trichopoulou, Antonia
name: Karakatsani, Anna
name: Martimianaki, Georgia
name: Palli, Domenico
name: Tagliabue, Giovanna
name: Panico, Salvatore
name: Tumino, Rosario
name: Sacerdote, Carlotta
name: Skeie, Guri
name: Merino, Susana
name: Bonet, Catalina
name: Rodríguez-Barranco, Miguel
name: Gil, Leire
name: Chirlaque, Maria-Dolores
name: Ardanaz, Eva
name: Myte, Robin
name: Hultdin, Johan
name: Perez-Cornago, Aurora
name: Aune, Dagfinn
name: Tsilidis, Konstantinos K.
name: Albanes, Demetrius
name: Baron, John A.
name: Berndt, Sonja I.
name: Bézieau, Stéphane
name: Brenner, Hermann
name: Campbell, Peter T.
name: Casey, Graham
name: Chan, Andrew T.
name: Chang-Claude, Jenny
name: Chanock, Stephen J.
name: Cotterchio, Michelle
name: Gallinger, Steven
name: Gruber, Stephen B.
name: Haile, Robert W.
name: Hampe, Jochen
name: Hoffmeister, Michael
name: Hopper, John L.
name: Hsu, Li
name: Huyghe, Jeroen R.
name: Jenkins, Mark A.
name: Joshi, Amit D.
name: Kampman, Ellen
name: Larsson, Susanna C.
name: Le Marchand, Loic
name: Li, Christopher I.
name: Li, Li
name: Lindblom, Annika
name: Lindor, Noralane M.
name: Martín, Vicente
name: Moreno, Victor
name: Newcomb, Polly A.
name: Offit, Kenneth
name: Ogino, Shuji
name: Parfrey, Patrick S.
name: Pharoah, Paul D. P.
name: Rennert, Gad
name: Sakoda, Lori C.
name: Schafmayer, Clemens
name: Schmit, Stephanie L.
name: Schoen, Robert E.
name: Slattery, Martha L.
name: Thibodeau, Stephen N.
name: Ulrich, Cornelia M.
name: Van Duijnhoven, Franzel J. B.
name: Weigl, Korbinian
name: Weinstein, Stephanie J.
name: White, Emily
name: Wolk, Alicja
name: Woods, Michael O.
name: Wu, Anna H.
name: Zhang, Xuehong
name: Ferrari, Pietro
name: Anton, Gabriele
name: Peters, Annette
name: Peters, Ulrike
name: Gunter, Marc J.
name: Wagner, Karl-Heinz
name: Freisling, Heinz
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: Research Article
Bilirubin
Cancer
Colorectal cancer
Anti-oxidants
Mendelian randomization analysis

description: 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 &lt; 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.