Genetically raised circulating bilirubin levels and risk of ten cancers: a Mendelian randomization study

Khoei, N. S. et al. (2021) Genetically raised circulating bilirubin levels and risk of ten cancers: a Mendelian randomization study. Cells, 10(2), 394. (doi: 10.3390/cells10020394) (PMID:33671849) (PMCID:PMC7918902)

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Abstract

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.

Item Type:Articles
Additional Information:This work was funded by the French National Cancer Institute (INCa, grant nr. 2016-043), the Austrian Science Fund (FWF, grant nr. P 29608), and the European Commission, BBMRILPC (FP7, grant nr. 313010). Robert Carreras-Torres was funded by the European Union’s Horizon 2020 research and innovation programs under the Marie Sklodowska-Curie grant agreement No 796216. We would also like to thank all other funding supports given in Supplementary Funding Sources and Acknowledgements. Study-specific funding sources are given in Supplementary Funding Sources and Acknowledgements. “Open Access Funding by the Austrian Science Fund (FWF)”.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jarrett, Professor Ruth
Creator Roles:
Jarrett, R.Writing – review and editing
Authors: Khoei, N. S., Carreras-Torres, R., Murphy, N., Gunter, M. J., Brennan, P., Smith-Byrne, K., O’Mara, T. A., Jarrett, R., Hjalgrim, H., Smedby, K. E., Cozen, W., Onel, K., Diepstra, A., Wagner, K.-H., and Freisling, H.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Cells
Publisher:MDPI
ISSN:2073-4409
ISSN (Online):2073-4409
Published Online:15 February 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cells 10(2):394
Publisher Policy:Reproduced under a Creative Commons License

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