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

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.

Associations between Prediagnostic Circulating Bilirubin Levels and Risk of Gastrointestinal Cancers in the UK Biobank

“…Sex hormones, which are known to influence UGT1A1 activity [ 46 ], and differences in UGT1A1 expression between men and women, leading to differential circulating levels [ 47 ], might partly explain the sex differences in pancreatic cancer risk. We previously reported suggestive evidence of differences between men and women related to risk of pancreatic cancer [ 48 ] and CRC [ 13 ] using a genetic instrument approach, yet opposite in direction (suggestive higher risk in men and lower risk in women) compared to the present analysis. Our sex-stratified findings for pancreatic cancer could therefore also be due to chance.…”

The Value of Blood-Based Measures of Liver Function and Urate in Lung Cancer Risk Prediction: A Cohort Study and Health Economic Analysis

“…Strong independent associations with lung cancer, particularly amongst people who smoke cigarettes, have been reported in large cohort studies [13][14][15][16]. One of the component measurements, serum bilirubin, was identified in metabolomic profiling as the only relevant biomarker for lung cancer [16] with subsequent genetic studies supporting causal relationships [17,18]. Although less frequently ordered by primary health care providers, urate measurements are also strongly associated with lung cancer amongst people who smoke [14].…”

Bile acids, bile pigments and colorectal cancer risk

“…Interestingly, epidemiological observations revealed an inverse correlation of serum bilirubin levels and CRC risk [58][59][60]. However, there are also conflicting reports showing that the relationship of bilirubin and CRC risk may be sex-dependent [61,62].…”