Seyed Khoei, NazlisadatJenab, MazdaMurphy, NeilBanbury, Barbara LCarreras-Torres, RobertViallon, VivianKühn, TilmanBueno-de-Mesquita, BasAleksandrova, KrasimiraCross, Amanda JWeiderpass, ElisabeteStepien, MagdalenaBulmer, AndrewTjønneland, AnneBoutron-Ruault, Marie-ChristineSeveri, GianlucaCarbonnel, FranckKatzke, VerenaBoeing, HeinerBergmann, Manuela MTrichopoulou, AntoniaKarakatsani, AnnaMartimianaki, GeorgiaPalli, DomenicoTagliabue, GiovannaPanico, SalvatoreTumino, RosarioSacerdote, CarlottaSkeie, GuriMerino, SusanaBonet, CatalinaRodríguez-Barranco, MiguelGil, LeireChirlaque, Maria-DoloresArdanaz, EvaMyte, RobinHultdin, JohanPerez-Cornago, AuroraAune, DagfinnTsilidis, Konstantinos KAlbanes, DemetriusBaron, John ABerndt, Sonja IBézieau, StéphaneBrenner, HermannCampbell, Peter TCasey, GrahamChan, Andrew TChang-Claude, JennyChanock, Stephen JCotterchio, MichelleGallinger, StevenGruber, Stephen BHaile, Robert WHampe, JochenHoffmeister, MichaelHopper, John LHsu, LiHuyghe, Jeroen RJenkins, Mark AJoshi, Amit DKampman, EllenLarsson, Susanna CLe Marchand, LoicLi, Christopher ILi, LiLindblom, AnnikaLindor, Noralane MMartín, VicenteMoreno, VictorNewcomb, Polly AOffit, KennethOgino, ShujiParfrey, Patrick SPharoah, Paul D PRennert, GadSakoda, Lori CSchafmayer, ClemensSchmit, Stephanie LSchoen, Robert ESlattery, Martha LThibodeau, Stephen NUlrich, Cornelia Mvan Duijnhoven, Franzel J BWeigl, KorbinianWeinstein, Stephanie JWhite, EmilyWolk, AlicjaWoods, Michael OWu, Anna HZhang, XuehongFerrari, PietroAnton, GabrielePeters, AnnettePeters, UlrikeGunter, Marc JWagner, Karl-HeinzFreisling, Heinz2023-02-092023-02-092020-07-09Seyed Khoei N, Jenab M, Murphy N, Banbury BL, Carreras-Torres R, Viallon V, et al. Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses. BMC Med. 2020 Sep 3;18(1):229.http://hdl.handle.net/10668/16196Bilirubin, 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. 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  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). 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Anti-oxidantsBilirubinCancerColorectal cancerMendelian randomization analysisAdultAgedBilirubinCase-Control StudiesColorectal NeoplasmsEuropeFemaleHumansMaleMendelian Randomization AnalysisMiddle AgedPolymorphism, Single NucleotideProspective StudiesRisk Factorsresearch article32878631open accessAnálisis de la aleatorización mendelianaBilirrubinaEstudios prospectivosEstudios de casos y controlesFactores de riesgoNeoplasias colorrectalesPolimorfismo de nucleótido simple10.1186/s12916-020-01703-w1741-7015PMC7469292https://doi.org/10.1186/s12916-020-01703-whttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469292/pdf