{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:59:46Z","timestamp":1792187986825,"version":"4.4.0"},"reference-count":60,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["29608"],"award-info":[{"award-number":["29608"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["2016-043"],"award-info":[{"award-number":["2016-043"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2019s 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\u2019s lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p &lt; 5 \u00d7 10\u22128) 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 (\u2248 4.4 \u00b5mol\/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin\u2019s lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73\u20130.99, P 0.04 and OR 0.64, 95% CI 0.42\u20130.99, 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\u20131.20, 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/cells10020394","type":"journal-article","created":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T02:35:23Z","timestamp":1613356523000},"page":"394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6003-7794","authenticated-orcid":false,"given":"Nazlisadat Seyed","family":"Seyed Khoei","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2925-734X","authenticated-orcid":false,"given":"Robert","family":"Carreras-Torres","sequence":"additional","affiliation":[{"name":"Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L\u2019Hospitalet de Llobregat, 8908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Murphy","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc J.","family":"Gunter","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Brennan","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Smith-Byrne","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Mariosa","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Mckay","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"O\u2019Mara","sequence":"additional","affiliation":[{"name":"Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0390-3478","authenticated-orcid":false,"given":"Ruth","family":"Jarrett","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Hjalgrim","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen, Denmark"},{"name":"Department of Hematology, Finsen Centre, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin E.","family":"Smedby","sequence":"additional","affiliation":[{"name":"Department of Medicine Solna, Division of Clinical Epidemiology, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Department of Hematology, Karolinska University Hospital, S-141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Cozen","sequence":"additional","affiliation":[{"name":"Departments of Preventive Medicine and Pathology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenan","family":"Onel","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9239-1050","authenticated-orcid":false,"given":"Arjan","family":"Diepstra","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1683-7265","authenticated-orcid":false,"given":"Karl-Heinz","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8648-4998","authenticated-orcid":false,"given":"Heinz","family":"Freisling","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 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