Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study

Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostat...

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Autores: Seyed Khoei, Nazlisadat, Carreras Torres, Robert, Murphy, Neil, Gunter, Marc J., Brennan, Paul, Smith-Byrne, Karl, Mariosa, Daniela, McKay, James D., O’Mara, Tracy, Jarrett, Ruth, Hjalgrim, Henrik, Smedby, Karin E., Cozen, Wendy, Onel, Kenan, Diepstra, Arjan, Wagner, Karl-Heinz, Freisling, Heinz, ECAC Group
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/175497
Acceso en línea:https://hdl.handle.net/2445/175497
Access Level:acceso abierto
Palabra clave:Càncer
Antioxidants
Factors de risc en les malalties
Cancer
Risk factors in diseases
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spelling Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization StudySeyed Khoei, NazlisadatCarreras Torres, RobertMurphy, NeilGunter, Marc J.Brennan, PaulSmith-Byrne, KarlMariosa, DanielaMcKay, James D.O’Mara, TracyJarrett, RuthHjalgrim, HenrikSmedby, Karin E.Cozen, WendyOnel, KenanDiepstra, ArjanWagner, Karl-HeinzFreisling, HeinzECAC GroupCàncerAntioxidantsFactors de risc en les malaltiesCancerAntioxidantsRisk factors in diseasesBilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10-8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99, P 0.04 and OR 0.64, 95% CI 0.42-0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.MDPI2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/175497Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/cells10020394Cells, 2021, vol. 10, num. 2https://doi.org/10.3390/cells10020394cc by (c) Seyed Khoei et al., 2021http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1754972026-05-27T06:46:51Z
dc.title.none.fl_str_mv Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
title Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
spellingShingle Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
Seyed Khoei, Nazlisadat
Càncer
Antioxidants
Factors de risc en les malalties
Cancer
Antioxidants
Risk factors in diseases
title_short Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
title_full Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
title_fullStr Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
title_full_unstemmed Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
title_sort Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study
dc.creator.none.fl_str_mv Seyed Khoei, Nazlisadat
Carreras Torres, Robert
Murphy, Neil
Gunter, Marc J.
Brennan, Paul
Smith-Byrne, Karl
Mariosa, Daniela
McKay, James D.
O’Mara, Tracy
Jarrett, Ruth
Hjalgrim, Henrik
Smedby, Karin E.
Cozen, Wendy
Onel, Kenan
Diepstra, Arjan
Wagner, Karl-Heinz
Freisling, Heinz
ECAC Group
author Seyed Khoei, Nazlisadat
author_facet Seyed Khoei, Nazlisadat
Carreras Torres, Robert
Murphy, Neil
Gunter, Marc J.
Brennan, Paul
Smith-Byrne, Karl
Mariosa, Daniela
McKay, James D.
O’Mara, Tracy
Jarrett, Ruth
Hjalgrim, Henrik
Smedby, Karin E.
Cozen, Wendy
Onel, Kenan
Diepstra, Arjan
Wagner, Karl-Heinz
Freisling, Heinz
ECAC Group
author_role author
author2 Carreras Torres, Robert
Murphy, Neil
Gunter, Marc J.
Brennan, Paul
Smith-Byrne, Karl
Mariosa, Daniela
McKay, James D.
O’Mara, Tracy
Jarrett, Ruth
Hjalgrim, Henrik
Smedby, Karin E.
Cozen, Wendy
Onel, Kenan
Diepstra, Arjan
Wagner, Karl-Heinz
Freisling, Heinz
ECAC Group
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Antioxidants
Factors de risc en les malalties
Cancer
Antioxidants
Risk factors in diseases
topic Càncer
Antioxidants
Factors de risc en les malalties
Cancer
Antioxidants
Risk factors in diseases
description Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10-8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99, P 0.04 and OR 0.64, 95% CI 0.42-0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/175497
url https://hdl.handle.net/2445/175497
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/10.3390/cells10020394
Cells, 2021, vol. 10, num. 2
https://doi.org/10.3390/cells10020394
dc.rights.none.fl_str_mv cc by (c) Seyed Khoei et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Seyed Khoei et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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