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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/2/394 |
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| author | Nazlisadat Seyed Khoei Robert Carreras-Torres Neil Murphy Marc J. Gunter Paul Brennan Karl Smith-Byrne Daniela Mariosa James Mckay Tracy A. O’Mara Ruth Jarrett Henrik Hjalgrim Karin E. Smedby Wendy Cozen Kenan Onel Arjan Diepstra Karl-Heinz Wagner Heinz Freisling |
| author_facet | Nazlisadat Seyed Khoei Robert Carreras-Torres Neil Murphy Marc J. Gunter Paul Brennan Karl Smith-Byrne Daniela Mariosa James Mckay Tracy A. O’Mara Ruth Jarrett Henrik Hjalgrim Karin E. Smedby Wendy Cozen Kenan Onel Arjan Diepstra Karl-Heinz Wagner Heinz Freisling |
| author_sort | Nazlisadat Seyed Khoei |
| collection | DOAJ |
| 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 (<i>p </i>< 5 × 10<sup>−8</sup>) 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 (<i>UGT1A1)</i> gene explained 16.9% and the remaining 114 SNPs (non-<i>UGT1A1</i> 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-<i>UGT1A1</i> 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, <i>P</i> 0.04 and OR 0.64, 95% CI 0.42–0.99, <i>p</i> 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, <i>p</i> 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. |
| first_indexed | 2024-03-09T00:52:26Z |
| format | Article |
| id | doaj.art-5dc51627a3324578b02e107488c620c6 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T00:52:26Z |
| publishDate | 2021-02-01 |
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| series | Cells |
| spelling | doaj.art-5dc51627a3324578b02e107488c620c62023-12-11T17:05:56ZengMDPI AGCells2073-44092021-02-0110239410.3390/cells10020394Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization StudyNazlisadat Seyed Khoei0Robert Carreras-Torres1Neil Murphy2Marc J. Gunter3Paul Brennan4Karl Smith-Byrne5Daniela Mariosa6James Mckay7Tracy A. O’Mara8Ruth Jarrett9Henrik Hjalgrim10Karin E. Smedby11Wendy Cozen12Kenan Onel13Arjan Diepstra14Karl-Heinz Wagner15Heinz Freisling16Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, AustriaColorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 8908 Barcelona, SpainNutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, FranceNutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, FranceGenomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, FranceGenomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, FranceGenomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, FranceGenomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, FranceDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Queensland, AustraliaInstitute of Infection, Immunity and Inflammation, MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, UKDepartment of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen, DenmarkDepartment of Medicine Solna, Division of Clinical Epidemiology, Karolinska Institutet, 171 77 Stockholm, SwedenDepartments of Preventive Medicine and Pathology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USADepartment of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 60637, USADepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 Groningen, The NetherlandsDepartment of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, AustriaNutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, FranceBilirubin, 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 (<i>p </i>< 5 × 10<sup>−8</sup>) 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 (<i>UGT1A1)</i> gene explained 16.9% and the remaining 114 SNPs (non-<i>UGT1A1</i> 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-<i>UGT1A1</i> 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, <i>P</i> 0.04 and OR 0.64, 95% CI 0.42–0.99, <i>p</i> 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, <i>p</i> 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.https://www.mdpi.com/2073-4409/10/2/394bilirubinUGT1A1Mendelian randomizationcancer risk |
| spellingShingle | Nazlisadat Seyed Khoei Robert Carreras-Torres Neil Murphy Marc J. Gunter Paul Brennan Karl Smith-Byrne Daniela Mariosa James Mckay Tracy A. O’Mara Ruth Jarrett Henrik Hjalgrim Karin E. Smedby Wendy Cozen Kenan Onel Arjan Diepstra Karl-Heinz Wagner Heinz Freisling Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study Cells bilirubin UGT1A1 Mendelian randomization cancer risk |
| title | 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_short | 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 |
| topic | bilirubin UGT1A1 Mendelian randomization cancer risk |
| url | https://www.mdpi.com/2073-4409/10/2/394 |
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