title: Circulating total bilirubin and risk of incident cardiovascular disease in the general population.
abstract: OBJECTIVE
  To assess the association of circulating total bilirubin and cardiovascular disease (CVD) risk in a new prospective study and to determine whether adding information on total bilirubin values to established cardiovascular risk factors is associated with improvement in prediction of CVD risk.
  
  
  RESULTS
  Circulating total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-stage Disease) prospective study of 7222 participants and 773 incident CVD events. Total bilirubin was log-linearly associated with CVD risk. Age- and sex-adjusted hazard ratio (95% confidence interval) for CVD per 1-SD increase in loge total bilirubin was 0.82 (0.76 to 0.88; P<0.001), which was minimally attenuated to 0.89 (0.82 to 0.96; P=0.003) after further adjustment for established risk factors. In a meta-analysis of 12 population-based prospective studies involving 9378 incident CVD cases, the pooled multivariate-adjusted relative risk (95% confidence interval) for CVD was 0.93 (0.90 to 0.97; P<0.001) per 1-SD increase in total bilirubin levels. The corresponding pooled risks for coronary heart disease and stroke were 0.95 (0.92 to 0.99; P=0.018) and 0.93 (0.88 to 0.98; P=0.006), respectively. Addition of information on total bilirubin to a CVD risk prediction model containing established risk factors was associated with a C-index change of 0.0013 (-0.0004 to 0.0029; P=0.13).
  
  
  CONCLUSIONS
  There is a log-linear inverse association between circulating total bilirubin level and CVD risk, which is independent of established risk factors. Nonetheless, inclusion of total bilirubin in the standard established risk factors panel provides no significant improvement in CVD risk prediction.
authors.affiliation: From the Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (S.K.K., R.C.); Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (S.K.K.); Departments of Nephrology Medicine (S.J.L.B., R.T.G.) and Endocrinology (R.P.F.D.), University of Groningen and University Medical Center, Groningen, The Netherlands. skk31@cantab.net.
authors.forename: Setor K
authors.initials: SK
authors.lastname: Kunutsor
authors.affiliation: From the Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (S.K.K., R.C.); Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (S.K.K.); Departments of Nephrology Medicine (S.J.L.B., R.T.G.) and Endocrinology (R.P.F.D.), University of Groningen and University Medical Center, Groningen, The Netherlands.
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.affiliation: From the Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (S.K.K., R.C.); Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (S.K.K.); Departments of Nephrology Medicine (S.J.L.B., R.T.G.) and Endocrinology (R.P.F.D.), University of Groningen and University Medical Center, Groningen, The Netherlands.
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Gansevoort
authors.affiliation: From the Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (S.K.K., R.C.); Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (S.K.K.); Departments of Nephrology Medicine (S.J.L.B., R.T.G.) and Endocrinology (R.P.F.D.), University of Groningen and University Medical Center, Groningen, The Netherlands.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: From the Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (S.K.K., R.C.); Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (S.K.K.); Departments of Nephrology Medicine (S.J.L.B., R.T.G.) and Endocrinology (R.P.F.D.), University of Groningen and University Medical Center, Groningen, The Netherlands.
authors.forename: Robin P F
authors.initials: RP
authors.lastname: Dullaart
mesh_terms: D000328:Adult; D000368:Aged; D001663:Bilirubin / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology*; D005260:Female; D006801:Humans; D015994:Incidence; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009426:Netherlands / Q000453:epidemiology; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001663:Bilirubin
keywords: cardiovascular diseases; meta-analysis; risk factors