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@ARTICLE{SeyedKhoei:163020,
      author       = {N. Seyed Khoei and M. Jenab and N. Murphy and B. L. Banbury
                      and R. Carreras-Torres and V. Viallon and T. Kühn$^*$ and
                      B. Bueno-de-Mesquita and K. Aleksandrova and A. J. Cross and
                      E. Weiderpass and M. Stepien and A. Bulmer and A.
                      Tjønneland and M.-C. Boutron-Ruault and G. Severi and F.
                      Carbonnel and V. Katzke$^*$ and H. Boeing and M. M. Bergmann
                      and A. Trichopoulou and A. Karakatsani and G. Martimianaki
                      and D. Palli and G. Tagliabue and S. Panico and R. Tumino
                      and C. Sacerdote and G. Skeie and S. Merino and C. Bonet and
                      M. Rodríguez-Barranco and L. Gil and M.-D. Chirlaque and E.
                      Ardanaz and R. Myte and J. Hultdin and A. Perez-Cornago and
                      D. Aune and K. K. Tsilidis and D. Albanes and J. A. Baron
                      and S. I. Berndt and S. Bézieau and H. Brenner$^*$ and P.
                      T. Campbell and G. Casey and A. T. Chan and J.
                      Chang-Claude$^*$ and S. J. Chanock and M. Cotterchio and S.
                      Gallinger and S. B. Gruber and R. W. Haile and J. Hampe and
                      M. Hoffmeister$^*$ and J. L. Hopper and L. Hsu and J. R.
                      Huyghe and M. A. Jenkins and A. D. Joshi and E. Kampman and
                      S. C. Larsson and L. Le Marchand and C. I. Li and L. Li and
                      A. Lindblom and N. M. Lindor and V. Martín and V. Moreno
                      and P. A. Newcomb and K. Offit and S. Ogino and P. S.
                      Parfrey and P. D. P. Pharoah and G. Rennert and L. C. Sakoda
                      and C. Schafmayer and S. L. Schmit and R. E. Schoen and M.
                      L. Slattery and S. N. Thibodeau and C. M. Ulrich and F. J.
                      B. van Duijnhoven and K. Weigl$^*$ and S. J. Weinstein and
                      E. White and A. Wolk and M. O. Woods and A. H. Wu and X.
                      Zhang and P. Ferrari and G. Anton and A. Peters and U.
                      Peters and M. J. Gunter and K.-H. Wagner and H. Freisling},
      title        = {{C}irculating bilirubin levels and risk of colorectal
                      cancer: serological and {M}endelian randomization analyses.},
      journal      = {BMC medicine},
      volume       = {18},
      number       = {1},
      issn         = {1741-7015},
      address      = {Heidelberg [u.a.]},
      publisher    = {Springer},
      reportid     = {DKFZ-2020-01811},
      pages        = {229},
      year         = {2020},
      abstract     = {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.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.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.},
      cin          = {C020 / C070 / C120 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)C020-20160331 / I:(DE-He78)C070-20160331 /
                      I:(DE-He78)C120-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32878631},
      pmc          = {pmc:PMC7469292},
      doi          = {10.1186/s12916-020-01703-w},
      url          = {https://inrepo02.dkfz.de/record/163020},
}