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Background Moderately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect antioxidant properties or residual confounding. Objective This study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank. Methods We instrumented serum total bilirubin level using two variants (rs887829 and rs4149056) that together explain ~40% of population-level variability and are linked to mild hereditary hyperbilirubinaemia. Lung cancer events occurring after recruitment were identified from national cancer registries. Observational and genetically instrumented incidence rate ratios (IRRs) and rate differences per 10 000 person-years (PYs) by smoking status were estimated. Results We included 377 294 participants (median bilirubin 8.1 mol/L (IQR 6.4-10.4)) and 2002 lung cancer events in the MR analysis. Each 5 U+00B5mol/L increase in observed bilirubin levels was associated with 1.2/10 000 PY decrease (95% CI 0.7 to 1.8) in lung cancer incidence. The corresponding MR estimate was a decrease of 0.8/10 000 PY (95% CI 0.1 to 1.4). The strongest associations were in current smokers where a 5 U+00B5mol/L increase in observed bilirubin levels was associated with a decrease in lung cancer incidence of 10.2/10 000 PY (95% CI 5.5 to 15.0) and an MR estimate of 6.4/10 000 PY (95% CI 1.4 to 11.5). For heavy smokers (U+226520/day), the MR estimate was an incidence decrease of 23.1/10 000 PY (95% CI 7.3 to 38.9). There was no association in never smokers and no mediation by respiratory function. Conclusion Genetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers.
The role of serum-based small molecule antioxidants in preventing and predicting age-related phenotypes and respiratory cancer
Human blood contains various small molecules with potent antioxidant properties including bilirubin, uric acid, vitamin C, vitamin E and beta-carotene and raised serum levels have been independently associated with a reduced risk of respiratory disease. However, whether these relationships are causal remains to be proven. Furthermore, the role of these molecules in improving risk stratification has not been evaluated.
The aims of the research are to establish whether people with genetically lower levels small-molecule antioxidants have worse respiratory and endothelial function and whether serum bilirubin and urate measures have any role in improving lung cancer prediction in smokers. Knowledge on whether serum antioxidants are causally related to respiratory/endothelial function could help us understand why some smokers succumb to respiratory disease while others remain comparatively healthy. In turn, this could help GPs identify high-risk smokers and detect lung cancer at an earlier stage by targeting chest screening. The research could also identify potential therapeutic targets for the primary prevention of respiratory diseases. Using the full cohort, we will investigate whether genetic variants known to influence levels of the five named antioxidants in section 1a above are also associated with baseline measures of respiratory function and arterial stiffness. We hypothesize that any effects will be stronger in smokers exposed to high levels of antioxidants and thus will test for interactions with smoking status. We will then investigate whether measuring bilirubin and uric acid levels can improve lung cancer risk prediction. Full cohort