Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

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

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 (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.

Keywords: Anti-oxidants; Bilirubin; Cancer; Colorectal cancer; Mendelian randomization analysis.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Scatter plots depicting the genetic association between total bilirubin levels and colorectal cancer risk. Per allele association of total bilirubin SNPs with inverse-normal-transformed bilirubin levels (x axis) and risk for colorectal cancer (y axis; logarithmic scale) in men (a) and in women (b), together with the likelihood-based MR estimate for the genetic instrument comprising of the 114 SNPs (dashed-blue line) and their 95% CI (dotted-blue lines)

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