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.