Genetically raised serum bilirubin levels and respiratory cancer: a cohort study using UK Biobank


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Laura Horsfall1,Stephen Burgess2,Ian Hall3,Irwin Nazareth1
1University College London, London, UK,2MRC Biostatistics Unit, Cambridge, UK,3University of Nottingham, Nottingham, UK



Moderately raised serum bilirubin levels are associated with lower rates of respiratory cancer in large observational studies. It is unclear whether these relationships reflect antioxidant properties of bilirubin protecting against the carcinogenic effect of smoke oxidants or are due to confounding by lifestyle factors. We report the results of the first large-scale analysis of the causal relationship between bilirubin levels and respiratory cancer using a Mendelian randomisation approach.


This research included unrelated participants of white British ancestry participating in the UK Biobank Resource. Average bilirubin levels in people homozygous for the minor T allele of rs887829 in the UDP-glucuronosyltransferase 1-1 gene are 8-10 ┬Ámol/l (80-100%) higher than those without this genotype. Using multivariable Poisson regression, we analysed the relationship between rs887829 T homozygosity and the incidence of respiratory cancers derived from national registers. The results were stratified by smoking behaviour with never smokers used as a negative control group.


The analysis included 363,059 people, 1,962,584 person-years (PYs) at risk and 1188 respiratory cancer events. One in ten participants were homozygous for the T allele of rs887829 (n=35,881). There was no relationship between the genotype and respiratory cancer in never smokers or people smoking less than 20 cigarettes per day. The incidence rate in people homozygous for rs887829 T allele smoking 20 or more cigarettes per day was 10 per 10,000 PYs versus 17 per 10,000 PYs for the other genotypes. The adjusted incidence rate was 43% lower in rs887829 TT homozygotes relative to the other genotypes (incidence rate ratio: 0.57; 95%CI: 0.38 to 0.86; p=0.0065). 


Moderately raised bilirubin may help protect people exposed to high levels of smoke oxidants against respiratory cancers. The role as a therapeutic target and a low-cost causal biomarker for disease risk stratification requires further research. Wellcome Trust funded:209207/Z/17/Z