title: Serum bilirubin and the risk of hypertension.
abstract: BACKGROUND
  Experimental studies suggest oxidative stress could lead to the development of hypertension. Serum bilirubin is a major contributor to the antioxidant capacity in blood plasma and has been identified as an independent cardiovascular risk factor in cohort studies. However, data on the relationship between bilirubin and blood pressure are scarce and inconclusive.
  
  
  METHODS
  We analysed data from the National Health and Nutrition Examination Surveys (NHANES) 1999-2012 (N=31069). Fifty multiple imputed data sets were generated and analysed to avoid selection/confounding bias due to excluding individuals/variables with missing values. A minimal sufficient adjustment set of variables (MSAS) needed to estimate the unconfounded effect of bilirubin on blood pressure and hypertension (systolic/diastolic blood pressure ≥ 140/90 mmHg or using antihypertensive medication) was identified using the back-door criterion and included in all regression models.
  
  
  RESULTS
  After adjustment for the MSAS variables, systolic blood pressure decreased progressively up to -2.5 mmHg (p<0.001) and the prevalence of hypertension was up to 25% lower (P<0.001) in those with bilirubin ≥ 1.0 mg/dl-the highest two deciles-compared with those with 0.1-0.4 mg/dl-the lowest decile. Sensitivity analyses showed these results were unlikely to be explained by residual confounding or selection bias.
  
  
  CONCLUSIONS
  High serum bilirubin may decrease the risk of hypertension by inactivating and inhibiting the synthesis of reactive oxygen species in vascular cells. Strategies to boost the bioavailability of circulating and tissue bilirubin or to mimic bilirubin's antioxidant properties could have a significant impact on prevention and control of hypertension as well as coronary heart disease.
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, China and Department of Population Health Sciences, University of Wisconsin in Madison, Madison, WI, USA Key Laboratory of Environmental Medicine Engineering, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, China and Department of Population Health Sciences, University of Wisconsin in Madison, Madison, WI, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Environmental Medicine Engineering, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, China and Department of Population Health Sciences, University of Wisconsin in Madison, Madison, WI, USA lebautista@wisc.edu.
authors.forename: Leonelo E
authors.initials: LE
authors.lastname: Bautista
mesh_terms: D000367:Age Factors; D001663:Bilirubin / Q000097:blood* / Q000502:physiology; D001794:Blood Pressure; D015986:Confounding Factors, Epidemiologic; D015438:Health Behavior; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000503:physiopathology; D009749:Nutrition Surveys; D018384:Oxidative Stress / Q000502:physiology; D015995:Prevalence; D011897:Random Allocation; D015203:Reproducibility of Results; D012307:Risk Factors; D012737:Sex Factors; D012959:Socioeconomic Factors
chemical_list: D001663:Bilirubin
keywords: Bilirubin; NHANES; antioxidants; blood pressure; direct acyclic graphs; multiple imputation; reactive oxygen species; sensitivity analysis