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 o...
| Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | article |
| Status: | Published version |
| Publication Date: | 2020 |
| Country: | España |
| Institution: | Universidad de Barcelona |
| Repository: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/173409 |
| Online Access: | https://hdl.handle.net/2445/173409 |
| Access Level: | Open access |
| Keyword: | Càncer colorectal Antioxidants Colorectal cancer |
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oai:diposit.ub.edu:2445/173409 |
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| dc.title.none.fl_str_mv |
Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses |
| title |
Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses |
| spellingShingle |
Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses Khoei, Nazlisadat Seyed Càncer colorectal Antioxidants Colorectal cancer Antioxidants |
| 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 |
| dc.creator.none.fl_str_mv |
Khoei, Nazlisadat Seyed Jenab, Mazda Murphy, Neil Banbury, Barbara L. Carreras Torres, Robert Viallon, Vivian Kühn, Tilman Bueno de Mesquita, H. Bas Aleksandrova, Krasimira Cross, Amanda J. Weiderpass, Elisabete Stepien, Magdalena Bulmer, Andrew Tjønneland, 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 Bonet, Catalina Rodríguez Barranco, Miguel Gil, Leire Chirlaque, María Dolores Ardanaz, Eva Myte, Robin Hultdin, Johan Pérez Cornago, Aurora Aune, Dagfinn Tsilidis, Konstantinos K. Albanes, Demetrius Baron, John A. Berndt, Sonja I. Bézieau, Stéphane 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. Marchand, Loïc Le Li, Christopher I. Li, Li Lindblom, Annika Lindor, Noralane M. Martín Sánchez, Vicente Moreno Aguado, Víctor 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 |
Khoei, Nazlisadat Seyed |
| author_facet |
Khoei, Nazlisadat Seyed Jenab, Mazda Murphy, Neil Banbury, Barbara L. Carreras Torres, Robert Viallon, Vivian Kühn, Tilman Bueno de Mesquita, H. Bas Aleksandrova, Krasimira Cross, Amanda J. Weiderpass, Elisabete Stepien, Magdalena Bulmer, Andrew Tjønneland, 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 Bonet, Catalina Rodríguez Barranco, Miguel Gil, Leire Chirlaque, María Dolores Ardanaz, Eva Myte, Robin Hultdin, Johan Pérez Cornago, Aurora Aune, Dagfinn Tsilidis, Konstantinos K. Albanes, Demetrius Baron, John A. Berndt, Sonja I. Bézieau, Stéphane 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. Marchand, Loïc Le Li, Christopher I. Li, Li Lindblom, Annika Lindor, Noralane M. Martín Sánchez, Vicente Moreno Aguado, Víctor 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_role |
author |
| author2 |
Jenab, Mazda Murphy, Neil Banbury, Barbara L. Carreras Torres, Robert Viallon, Vivian Kühn, Tilman Bueno de Mesquita, H. Bas Aleksandrova, Krasimira Cross, Amanda J. Weiderpass, Elisabete Stepien, Magdalena Bulmer, Andrew Tjønneland, 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 Bonet, Catalina Rodríguez Barranco, Miguel Gil, Leire Chirlaque, María Dolores Ardanaz, Eva Myte, Robin Hultdin, Johan Pérez Cornago, Aurora Aune, Dagfinn Tsilidis, Konstantinos K. Albanes, Demetrius Baron, John A. Berndt, Sonja I. Bézieau, Stéphane 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. Marchand, Loïc Le Li, Christopher I. Li, Li Lindblom, Annika Lindor, Noralane M. Martín Sánchez, Vicente Moreno Aguado, Víctor 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 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Càncer colorectal Antioxidants Colorectal cancer Antioxidants |
| topic |
Càncer colorectal Antioxidants Colorectal cancer Antioxidants |
| 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. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/173409 |
| url |
https://hdl.handle.net/2445/173409 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1186/s12916-020-01703-w BMC Medicine, 2020, vol. 18 https://doi.org/10.1186/s12916-020-01703-w |
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cc by (c) Khoei et al., 2020 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess |
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cc by (c) Khoei et al., 2020 http://creativecommons.org/licenses/by/3.0/es/ |
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openAccess |
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application/pdf |
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BioMed Central |
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BioMed Central |
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Articles publicats en revistes (Ciències Clíniques) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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1869420064277528576 |
| spelling |
Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analysesKhoei, Nazlisadat SeyedJenab, MazdaMurphy, NeilBanbury, Barbara L.Carreras Torres, RobertViallon, VivianKühn, TilmanBueno de Mesquita, H. BasAleksandrova, KrasimiraCross, Amanda J.Weiderpass, ElisabeteStepien, MagdalenaBulmer, AndrewTjønneland, AnneBoutron-Ruault, Marie-ChristineSeveri, GianlucaCarbonnel, FranckKatzke, VerenaBoeing, HeinerBergmann, Manuela M.Trichopoulou, AntoniaKarakatsani, AnnaMartimianaki, GeorgiaPalli, DomenicoTagliabue, GiovannaPanico, SalvatoreTumino, RosarioSacerdote, CarlottaSkeie, GuriMerino, SusanaBonet Bonet, CatalinaRodríguez Barranco, MiguelGil, LeireChirlaque, María DoloresArdanaz, EvaMyte, RobinHultdin, JohanPérez Cornago, AuroraAune, DagfinnTsilidis, Konstantinos K.Albanes, DemetriusBaron, John A.Berndt, Sonja I.Bézieau, StéphaneBrenner, HermannCampbell, Peter T.Casey, GrahamChan, Andrew T.Chang Claude, JennyChanock, Stephen J.Cotterchio, MichelleGallinger, StevenGruber, Stephen B.Haile, Robert W.Hampe, JochenHoffmeister, MichaelHopper, John L.Hsu, LiHuyghe, Jeroen R.Jenkins, Mark A.Joshi, Amit D.Kampman, EllenLarsson, Susanna C.Marchand, Loïc LeLi, Christopher I.Li, LiLindblom, AnnikaLindor, Noralane M.Martín Sánchez, VicenteMoreno Aguado, VíctorNewcomb, Polly A.Offit, KennethOgino, ShujiParfrey, Patrick S.Pharoah, Paul D. P.Rennert, GadSakoda, Lori C.Schafmayer, ClemensSchmit, Stephanie L.Schoen, Robert E.Slattery, Martha L.Thibodeau, Stephen N.Ulrich, Cornelia M.van Duijnhoven, Franzel J. B.Weigl, KorbinianWeinstein, Stephanie J.White, EmilyWolk, AlicjaWoods, Michael O.Wu, Anna H.Zhang, XuehongFerrari, PietroAnton, GabrielePeters, AnnettePeters, UlrikeGunter, Marc J.Wagner, Karl-HeinzFreisling, HeinzCàncer colorectalAntioxidantsColorectal cancerAntioxidantsBackground: 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 Central2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/173409Articles publicats en revistes (Ciències Clíniques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s12916-020-01703-wBMC Medicine, 2020, vol. 18https://doi.org/10.1186/s12916-020-01703-wcc by (c) Khoei et al., 2020http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1734092026-05-27T06:46:51Z |
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15.301603 |