@article{3103884,
    title = "Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses",
    author = "Seyed Khoei, N. and Jenab, M. and Murphy, N. and Banbury, B.L. and Carreras-Torres, R. and Viallon, V. and Kühn, T. and Bueno-De-Mesquita, B. and Aleksandrova, K. and Cross, A.J. and Weiderpass, E. and Stepien, M. and Bulmer, A. and Tjønneland, A. and Boutron-Ruault, M.-C. and Severi, G. and Carbonnel, F. and Katzke, V. and Boeing, H. and Bergmann, M.M. and Trichopoulou, A. and Karakatsani, A. and Martimianaki, G. and Palli, D. and Tagliabue, G. and Panico, S. and Tumino, R. and Sacerdote, C. and Skeie, G. and Merino, S. and Bonet, C. and Rodríguez-Barranco, M. and Gil, L. and Chirlaque, M.-D. and Ardanaz, E. and Myte, R. and Hultdin, J. and Perez-Cornago, A. and Aune, D. and Tsilidis, K.K. and Albanes, D. and Baron, J.A. and Berndt, S.I. and Bézieau, S. and Brenner, H. and Campbell, P.T. and Casey, G. and Chan, A.T. and Chang-Claude, J. and Chanock, S.J. and Cotterchio, M. and Gallinger, S. and Gruber, S.B. and Haile, R.W. and Hampe, J. and Hoffmeister, M. and Hopper, J.L. and Hsu, L. and Huyghe, J.R. and Jenkins, M.A. and Joshi, A.D. and Kampman, E. and Larsson, S.C. and Le Marchand, L. and Li, C.I. and Li, L. and Lindblom, A. and Lindor, N.M. and Martín, V. and Moreno, V. and Newcomb, P.A. and Offit, K. and Ogino, S. and Parfrey, P.S. and Pharoah, P.D.P. and Rennert, G. and Sakoda, L.C. and Schafmayer, C. and Schmit, S.L. and Schoen, R.E. and Slattery, M.L. and Thibodeau, S.N. and Ulrich, C.M. and Van Duijnhoven, F.J.B. and Weigl, K. and Weinstein, S.J. and White, E. and Wolk, A. and Woods, M.O. and Wu, A.H. and Zhang, X. and Ferrari, P. and Anton, G. and Peters, A. and Peters, U. and Gunter, M.J. and Wagner, K.-H. and Freisling, H.",
    journal = "BMC Medicine",
    year = "2020",
    volume = "18",
    number = "1",
    publisher = "BioMed Central Ltd.",
    issn = "1741-7015",
    doi = "10.1186/s12916-020-01703-w",
    keywords = "bilirubin;  glucuronosyltransferase 1A1;  bilirubin, adult;  Article;  bilirubin blood level;  cancer risk;  case control study;  colorectal cancer;  controlled study;  female;  gene;  gene identification;  genetic association;  genetic risk;  high performance liquid chromatography;  high risk population;  human;  major clinical study;  male;  Mendelian randomization analysis;  middle aged;  predictive value;  risk assessment;  sex difference;  single nucleotide polymorphism;  UGT1A1 gene;  aged;  blood;  clinical trial;  colorectal tumor;  Europe;  Mendelian randomization analysis;  metabolism;  multicenter study;  procedures;  prospective study;  risk factor, Adult;  Aged;  Bilirubin;  Case-Control Studies;  Colorectal Neoplasms;  Europe;  Female;  Humans;  Male;  Mendelian Randomization Analysis;  Middle Aged;  Polymorphism, Single Nucleotide;  Prospective Studies;  Risk Factors",
    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 (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 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 (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. © 2020 The Author(s)."
}