Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses
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...
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R Medicine (General) Seyed Khoei, Nazlisadat Jenab, Mazda Murphy, Neil Banbury, Barbara L. Carreras-Torres, Robert Viallon, Vivian Kuehn, Tilman Bueno-de-Mesquita, Bas Aleksandrova, Krasimira Cross, Amanda J. Weiderpass, Elisabete Stepien, Magdalena Bulmer, Andrew Tjonneland, Anne Boutron-Ruault, Marie-Christine Severi, Gianluca Carbonnel, Franck Katzke, Verena Boeing, Heiner Bergmann, Manuela M. Trichopoulou, Antonia Karakatsani, Anna Martimianaki, Georgia Palli, Domenico Tagliabue, Giovanna Panico, Salvatore Tumino, Rosario Sacerdote, Carlotta Skeie, Guri Merino, Susana Bonet, Catalina Rodriguez-Barranco, Miguel Gil, Leire Chirlaque, Maria-Dolores Ardanaz, Eva Myte, Robin Hultdin, Johan Perez-Cornago, Aurora Aune, Dagfinn Tsilidis, Konstantinos Albanes, - Baron, John A. Berndt, Sonja I. Bezieau, Stephane Brenner, Hermann Campbell, Peter T. Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen J. Cotterchio, Michelle Gallinger, Steven Gruber, Stephen B. Haile, Robert W. Hampe, Jochen Hoffmeister, Michael Hopper, John L. Hsu, Li Huyghe, Jeroen R. Jenkins, Mark A. Joshi, Amit D. Kampman, Ellen Larsson, Susanna C. Le Marchand, Loic Li, Christopher I. Li, Li Lindblom, Annika Lindor, Noralane M. Martin, Vicente Moreno, Victor Newcomb, Polly A. Offit, Kenneth Ogino, Shuji Parfrey, Patrick S. Pharoah, Paul D. P. Rennert, Gad Sakoda, Lori C. Schafmayer, Clemens Schmit, Stephanie L. Schoen, Robert E. Slattery, Martha L. Thibodeau, Stephen N. Ulrich, Cornelia M. van Duijnhoven, Franzel J. B. Weigl, Korbinian Weinstein, Stephanie J. White, Emily Wolk, Alicja Woods, Michael O. Wu, Anna H. Zhang, Xuehong Ferrari, Pietro Anton, Gabriele Peters, Annette Peters, Ulrike Gunter, Marc J. Wagner, Karl-Heinz Freisling, Heinz Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses |
| description |
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 x 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 mainUGT1A1SNP (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. |
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| author |
Seyed Khoei, Nazlisadat Jenab, Mazda Murphy, Neil Banbury, Barbara L. Carreras-Torres, Robert Viallon, Vivian Kuehn, Tilman Bueno-de-Mesquita, Bas Aleksandrova, Krasimira Cross, Amanda J. Weiderpass, Elisabete Stepien, Magdalena Bulmer, Andrew Tjonneland, Anne Boutron-Ruault, Marie-Christine Severi, Gianluca Carbonnel, Franck Katzke, Verena Boeing, Heiner Bergmann, Manuela M. Trichopoulou, Antonia Karakatsani, Anna Martimianaki, Georgia Palli, Domenico Tagliabue, Giovanna Panico, Salvatore Tumino, Rosario Sacerdote, Carlotta Skeie, Guri Merino, Susana Bonet, Catalina Rodriguez-Barranco, Miguel Gil, Leire Chirlaque, Maria-Dolores Ardanaz, Eva Myte, Robin Hultdin, Johan Perez-Cornago, Aurora Aune, Dagfinn Tsilidis, Konstantinos Albanes, - Baron, John A. Berndt, Sonja I. Bezieau, Stephane Brenner, Hermann Campbell, Peter T. Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen J. Cotterchio, Michelle Gallinger, Steven Gruber, Stephen B. Haile, Robert W. Hampe, Jochen Hoffmeister, Michael Hopper, John L. Hsu, Li Huyghe, Jeroen R. Jenkins, Mark A. Joshi, Amit D. Kampman, Ellen Larsson, Susanna C. Le Marchand, Loic Li, Christopher I. Li, Li Lindblom, Annika Lindor, Noralane M. Martin, Vicente Moreno, Victor Newcomb, Polly A. Offit, Kenneth Ogino, Shuji Parfrey, Patrick S. Pharoah, Paul D. P. Rennert, Gad Sakoda, Lori C. Schafmayer, Clemens Schmit, Stephanie L. Schoen, Robert E. Slattery, Martha L. Thibodeau, Stephen N. Ulrich, Cornelia M. van Duijnhoven, Franzel J. B. Weigl, Korbinian Weinstein, Stephanie J. White, Emily Wolk, Alicja Woods, Michael O. Wu, Anna H. Zhang, Xuehong Ferrari, Pietro Anton, Gabriele Peters, Annette Peters, Ulrike Gunter, Marc J. Wagner, Karl-Heinz Freisling, Heinz |
| author_facet |
Seyed Khoei, Nazlisadat Jenab, Mazda Murphy, Neil Banbury, Barbara L. Carreras-Torres, Robert Viallon, Vivian Kuehn, Tilman Bueno-de-Mesquita, Bas Aleksandrova, Krasimira Cross, Amanda J. Weiderpass, Elisabete Stepien, Magdalena Bulmer, Andrew Tjonneland, Anne Boutron-Ruault, Marie-Christine Severi, Gianluca Carbonnel, Franck Katzke, Verena Boeing, Heiner Bergmann, Manuela M. Trichopoulou, Antonia Karakatsani, Anna Martimianaki, Georgia Palli, Domenico Tagliabue, Giovanna Panico, Salvatore Tumino, Rosario Sacerdote, Carlotta Skeie, Guri Merino, Susana Bonet, Catalina Rodriguez-Barranco, Miguel Gil, Leire Chirlaque, Maria-Dolores Ardanaz, Eva Myte, Robin Hultdin, Johan Perez-Cornago, Aurora Aune, Dagfinn Tsilidis, Konstantinos Albanes, - Baron, John A. Berndt, Sonja I. Bezieau, Stephane Brenner, Hermann Campbell, Peter T. Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen J. Cotterchio, Michelle Gallinger, Steven Gruber, Stephen B. Haile, Robert W. Hampe, Jochen Hoffmeister, Michael Hopper, John L. Hsu, Li Huyghe, Jeroen R. Jenkins, Mark A. Joshi, Amit D. Kampman, Ellen Larsson, Susanna C. Le Marchand, Loic Li, Christopher I. Li, Li Lindblom, Annika Lindor, Noralane M. Martin, Vicente Moreno, Victor Newcomb, Polly A. Offit, Kenneth Ogino, Shuji Parfrey, Patrick S. Pharoah, Paul D. P. Rennert, Gad Sakoda, Lori C. Schafmayer, Clemens Schmit, Stephanie L. Schoen, Robert E. Slattery, Martha L. Thibodeau, Stephen N. Ulrich, Cornelia M. van Duijnhoven, Franzel J. B. Weigl, Korbinian Weinstein, Stephanie J. White, Emily Wolk, Alicja Woods, Michael O. Wu, Anna H. Zhang, Xuehong Ferrari, Pietro Anton, Gabriele Peters, Annette Peters, Ulrike Gunter, Marc J. Wagner, Karl-Heinz Freisling, Heinz |
| author_sort |
Seyed Khoei, Nazlisadat |
| title |
Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses |
| title_short |
Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses |
| title_full |
Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses |
| title_fullStr |
Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses |
| title_full_unstemmed |
Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses |
| title_sort |
circulating bilirubin levels and risk of colorectal cancer: serological and mendelian randomization analyses |
| publisher |
BioMed Central Ltd |
| publishDate |
2020 |
| url |
http://eprints.um.edu.my/36409/ |
| _version_ |
1814933196836438016 |
| spelling |
my.um.eprints.364092024-10-28T07:19:10Z http://eprints.um.edu.my/36409/ Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses Seyed Khoei, Nazlisadat Jenab, Mazda Murphy, Neil Banbury, Barbara L. Carreras-Torres, Robert Viallon, Vivian Kuehn, Tilman Bueno-de-Mesquita, Bas Aleksandrova, Krasimira Cross, Amanda J. Weiderpass, Elisabete Stepien, Magdalena Bulmer, Andrew Tjonneland, Anne Boutron-Ruault, Marie-Christine Severi, Gianluca Carbonnel, Franck Katzke, Verena Boeing, Heiner Bergmann, Manuela M. Trichopoulou, Antonia Karakatsani, Anna Martimianaki, Georgia Palli, Domenico Tagliabue, Giovanna Panico, Salvatore Tumino, Rosario Sacerdote, Carlotta Skeie, Guri Merino, Susana Bonet, Catalina Rodriguez-Barranco, Miguel Gil, Leire Chirlaque, Maria-Dolores Ardanaz, Eva Myte, Robin Hultdin, Johan Perez-Cornago, Aurora Aune, Dagfinn Tsilidis, Konstantinos Albanes, - Baron, John A. Berndt, Sonja I. Bezieau, Stephane Brenner, Hermann Campbell, Peter T. Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen J. Cotterchio, Michelle Gallinger, Steven Gruber, Stephen B. Haile, Robert W. Hampe, Jochen Hoffmeister, Michael Hopper, John L. Hsu, Li Huyghe, Jeroen R. Jenkins, Mark A. Joshi, Amit D. Kampman, Ellen Larsson, Susanna C. Le Marchand, Loic Li, Christopher I. Li, Li Lindblom, Annika Lindor, Noralane M. Martin, Vicente Moreno, Victor Newcomb, Polly A. Offit, Kenneth Ogino, Shuji Parfrey, Patrick S. Pharoah, Paul D. P. Rennert, Gad Sakoda, Lori C. Schafmayer, Clemens Schmit, Stephanie L. Schoen, Robert E. Slattery, Martha L. Thibodeau, Stephen N. Ulrich, Cornelia M. van Duijnhoven, Franzel J. B. Weigl, Korbinian Weinstein, Stephanie J. White, Emily Wolk, Alicja Woods, Michael O. Wu, Anna H. Zhang, Xuehong Ferrari, Pietro Anton, Gabriele Peters, Annette Peters, Ulrike Gunter, Marc J. Wagner, Karl-Heinz Freisling, Heinz R Medicine (General) 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 x 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 mainUGT1A1SNP (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. BioMed Central Ltd 2020-09 Article PeerReviewed Seyed Khoei, Nazlisadat and Jenab, Mazda and Murphy, Neil and Banbury, Barbara L. and Carreras-Torres, Robert and Viallon, Vivian and Kuehn, Tilman and Bueno-de-Mesquita, Bas and Aleksandrova, Krasimira and Cross, Amanda J. and Weiderpass, Elisabete and Stepien, Magdalena and Bulmer, Andrew and Tjonneland, Anne and Boutron-Ruault, Marie-Christine and Severi, Gianluca and Carbonnel, Franck and Katzke, Verena and Boeing, Heiner and Bergmann, Manuela M. and Trichopoulou, Antonia and Karakatsani, Anna and Martimianaki, Georgia and Palli, Domenico and Tagliabue, Giovanna and Panico, Salvatore and Tumino, Rosario and Sacerdote, Carlotta and Skeie, Guri and Merino, Susana and Bonet, Catalina and Rodriguez-Barranco, Miguel and Gil, Leire and Chirlaque, Maria-Dolores and Ardanaz, Eva and Myte, Robin and Hultdin, Johan and Perez-Cornago, Aurora and Aune, Dagfinn and Tsilidis, Konstantinos and Albanes, - and Baron, John A. and Berndt, Sonja I. and Bezieau, Stephane and Brenner, Hermann and Campbell, Peter T. and Casey, Graham and Chan, Andrew T. and Chang-Claude, Jenny and Chanock, Stephen J. and Cotterchio, Michelle and Gallinger, Steven and Gruber, Stephen B. and Haile, Robert W. and Hampe, Jochen and Hoffmeister, Michael and Hopper, John L. and Hsu, Li and Huyghe, Jeroen R. and Jenkins, Mark A. and Joshi, Amit D. and Kampman, Ellen and Larsson, Susanna C. and Le Marchand, Loic and Li, Christopher I. and Li, Li and Lindblom, Annika and Lindor, Noralane M. and Martin, Vicente and Moreno, Victor and Newcomb, Polly A. and Offit, Kenneth and Ogino, Shuji and Parfrey, Patrick S. and Pharoah, Paul D. P. and Rennert, Gad and Sakoda, Lori C. and Schafmayer, Clemens and Schmit, Stephanie L. and Schoen, Robert E. and Slattery, Martha L. and Thibodeau, Stephen N. and Ulrich, Cornelia M. and van Duijnhoven, Franzel J. B. and Weigl, Korbinian and Weinstein, Stephanie J. and White, Emily and Wolk, Alicja and Woods, Michael O. and Wu, Anna H. and Zhang, Xuehong and Ferrari, Pietro and Anton, Gabriele and Peters, Annette and Peters, Ulrike and Gunter, Marc J. and Wagner, Karl-Heinz and Freisling, Heinz (2020) Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses. BMC Medicine, 18 (1). ISSN 17417015, DOI https://doi.org/10.1186/s12916-020-01703-w <https://doi.org/10.1186/s12916-020-01703-w>. 10.1186/s12916-020-01703-w |
| score |
13.211869 |