Interplay of Serum Bilirubin and Tobacco Smoking with Lung and Head and Neck Cancers in a Diverse, EHR-linked Los Angeles Biobank

Background Bilirubin is a potent antioxidant with a protective role in many diseases. We examined the relationships between serum bilirubin (SB) levels, tobacco smoking (a known cause of low SB), and aerodigestive cancers, grouped as lung (LC) and head and neck (HNC). Methods We examined the associations between SB, LC and HNC using data from 393,210 participants from UCLA Health, employing regression models, propensity score matching, and polygenic scores. Results Current tobacco smokers showed lower SB (-0.04mg/dL, 95% CI: [-0.04, -0.03]), compared to never-smokers. Lower SB levels were observed in HNC and LC cases (-0.10 mg/dL, [-0.13, -0.09] and -0.09 mg/dL, CI [-0.1, -0.07] respectively) compared to cancer-free controls with the effect persisting after adjusting for smoking. SB levels were inversely associated with HNC and LC risk (ORs per SD change in SB: 0.64, CI [0.59,0.69] and 0.57, CI [0.43,0.75], respectively). Lastly, a polygenic score (PGS) for SB was associated with LC (OR per SD change of SB-PGS: 0.71, CI [0.67, 0.76]). Conclusions Low SB levels are associated with an increased risk of both HNC and LC, independent of the effect of tobacco smoking with tobacco smoking demonstrating a strong interaction with SB on LC risk. Additionally, genetically predicted low SB (from polygenic scores) is negatively associated with LC. Impact These findings suggest that SB could serve as a potential early biomarker for LC and HNC. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement VV is funded by NIH/NIDCR 5K12DE027830. The ATLAS Community Health Initiative is supported by UCLA Health, the David Geffen School of Medicine, and a grant from the UCLA Clinical and Translational Science Institute (UL1TR001881). KB is funded by an NIH 5T32H007895 grant. BP was partially supported by NIH awards R01 HG009120, R01 MH115676, R01 CA251555, R01 AI153827, R01 HG006399, R01 CA244670, and U01 HG011715. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Patient Recruitment and Sample Collection for Precision Health Activities at UCLA is an approved study by the UCLA Institutional Review Board (UCLA IRB #17-001013). All participants provided informed consent to participate in the research. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript [https://github.com/drvidhya/bili\_hnc\_lc][1] [1]: https://github.com/drvidhya/bili_hnc_lc