Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

Abstract

BackgroundModerately 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.ObjectiveThis study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank.MethodsWe 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.ResultsWe included 377 294 participants (median bilirubin 8.1 μmol/L (IQR 6.4–10.4)) and 2002 lung cancer events in the MR analysis. Each 5 μmol/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 μmol/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 (≥20/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.ConclusionGenetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers.

Gilbert’s syndrome, circulating bilirubin and lung cancer: a genetic advantage?

“…In their article published in this issue of Thorax , Horsfall and colleagues7 used data from the UK Biobank that included more than 350 000 men and women aged 40–69 years and recruited between 2006 and 2010 in different regions in the UK, to study potential causal relationships between serum total bilirubin and lung cancer incidence.…”

“…In their exemplarily well-designed observational study, Horsfall and colleagues report that each 5 µmol/L increment in circulating bilirubin was associated with 1.2/10 000 person-years decrease (95% CI: 0.7 to 1.8) in overall lung cancer incidence 7. After stratification by smoking status, a clear dose–response association became evident with the strongest reduction in predicted lung cancer incidence (−18.2/10 000 (95% CI: −33.3 to −3.4)) observed among current heavy smokers, who reported smoking 20 or more cigarettes per day.…”

“…Horsfall and colleagues7 addressed these potential shortcomings by complementing the serological analysis with an instrumental variable approach, in this context also referred to as Mendelian randomisation (MR),11 using single nucleotide polymorphisms (SNPs) robustly associated with circulating bilirubin concentrations. Provided that the main assumptions of MR hold, the obtained associations should be unbiased with regard to confounding and reverse causation.…”

“…This is the main strength of the work by Horsfall and colleagues, because their estimates of the genetic approach mirror the results of the serological approach as described above. Their conclusion that ‘ adult smokers in the UK Biobank with genetically raised bilirubin have lower rates of lung cancer’ 7 is therefore based on strong evidence and consistent with the endogenous antioxidant hypothesis of bilirubin.…”

Serum bilirubin and chronic obstructive pulmonary disease (COPD): a systematic review

“…They found associations with higher FEV 1 and FVC, a relationship which was strongest among heavy smokers who would be at greatest risk of developing COPD [ 14 ]. In an analysis of UK Biobank data, Horsfall et al also found that genetic changes associated with higher bilirubin levels are associated with a decreased risk of lung cancer, a relationship that was also strongest in heavy smokers [ 36 ]. The degree of increase in bilirubin and duration of therapy that would be needed to improve COPD and respiratory health outcomes remain unknown, and would need to be investigated in interventional trials.…”