title: The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling.
abstract: OBJECTIVE
  We aimed to identify serum metabolites as potential valuable biomarkers for lung cancer and to improve risk stratification in smokers.
  
  
  METHODS
  We performed global metabolomic profiling followed by targeted validation of individual metabolites in a case-control design of 386 lung cancer cases and 193 matched controls. We then validated bilirubin, which consistently showed significant differential levels in cases and controls, as a risk marker for lung cancer incidence and mortality in a large prospective cohort composed of 425,660 participants.
  
  
  RESULTS
  Through global metabolomic profiling and following targeted validation, bilirubin levels consistently showed a statistically significant difference among healthy controls and lung cancer cases. In the prospective cohort, the inverse association was only seen in male smokers, regardless of smoking pack-years and intensity. Compared with male smokers in the highest bilirubin group (>1 mg/dL), those in the lowest bilirubin group (<0.75 mg/dL) had 55% and 66% increase in risks of lung cancer incidence and mortality, respectively. For every 0.1 mg/dL decrease of bilirubin, the risks for lung cancer incidence and mortality increased by 5% and 6% in male smokers, respectively (both P < 0.001). There was a significant interaction between low serum bilirubin level and smoking on lung cancer risk (Pinteraction = 0.001).
  
  
  CONCLUSIONS
  Low levels of serum bilirubin are associated with higher risks of lung cancer incidence and mortality in male smokers and can be used to identify higher risk smokers for lung cancer.
authors.affiliation: Institute of Population Health Science, National Health Research Institutes, Zhunan, Taiwan. China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chi-Pang
authors.initials: CP
authors.lastname: Wen
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Fanmao
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas.
authors.forename: Dong
authors.initials: D
authors.lastname: Liang
authors.affiliation: Department of Radiological Sciences, University of California at Irvine, Irvine, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wen
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Heath
authors.initials: H
authors.lastname: Skinner
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xia
authors.initials: X
authors.lastname: Pu
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Digestive Disease Center, Show-Chwan Memorial Hospital, Changhua, Taiwan.
authors.forename: Chien-Hua
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute of Population Health Science, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chao Agnes
authors.initials: CA
authors.lastname: Hsiung
authors.affiliation: Institute of Population Health Science, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Min Kuang
authors.initials: MK
authors.lastname: Tsai
authors.affiliation: MJ Health Management Institution, Taipei, Taiwan.
authors.forename: Chwen Keng
authors.initials: CK
authors.lastname: Tsao
authors.affiliation: UC San Diego Moores Cancer Center, San Diego, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. xwu@mdanderson.org.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D001663:Bilirubin / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000302:isolation & purification; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000401:mortality / Q000473:pathology; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D012307:Risk Factors; D012907:Smoking / Q000097:blood* / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D001663:Bilirubin