title: Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study.
abstract: BACKGROUND
  Although HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity-a prototypical measure of HDL function-has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain.
  
  
  METHODS
  We measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40-79 years, assessed in 1993-97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB-depleted serum from study participants.
  
  
  RESULTS
  Cholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0·40; p<0·0001) and apoA-I concentration (r=0·22; p<0·0001). It was also inversely correlated with type 2 diabetes (r=-0·18; p<0·0001) and positively correlated with alcohol consumption (r=0·12; p<0·0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0·64, 95% CI 0·51-0·80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0·80 (95% CI 0·70-0·90) for a per-SD change in cholesterol efflux capacity.
  
  
  CONCLUSIONS
  HDL cholesterol efflux capacity might provide an alternative mechanism for therapeutic modulation of the HDL pathway beyond HDL cholesterol concentration to help reduce risk of coronary heart disease.
  
  
  BACKGROUND
  US National Institutes of Health, UK Medical Research Council, Cancer Research UK.
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Non-Communicable Diseases, Karachi, Pakistan. Electronic address: saleheen@upenn.edu.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Scott
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Sundas
authors.initials: S
authors.lastname: Javad
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Amrith
authors.initials: A
authors.lastname: Rodrigues
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Antonino
authors.initials: A
authors.lastname: Picataggi
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniya
authors.initials: D
authors.lastname: Lukmanova
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Mucksavage
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Billheimer
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Cardiology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.affiliation: Institute of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Wareham
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: rader@mail.med.upenn.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood*; D003327:Coronary Disease / Q000097:blood* / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D008076:Cholesterol, HDL