title: Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility.
abstract: BACKGROUND
  In contrast to clear associations between variants in genes participating in low-density lipoprotein metabolism and cardiovascular disease risk, such associations for high-density lipoprotein (HDL)-related genes are not well supported by recent large studies. We aimed to determine whether genetic variants at the locus encoding phospholipid transfer protein (PLTP), a protein involved in HDL remodeling, underlie altered PLTP activity, HDL particle concentration and size, and cardiovascular disease risk.
  
  
  RESULTS
  We assessed associations between 6 PLTP tagging single nucleotide polymorphisms and PLTP activity in 2 studies (combined n=384) and identified 2 variants that show reproducible associations with altered plasma PLTP activity. A gene score based on these variants is associated with lower hepatic PLTP transcription (P=3.2x10(-18)) in a third study (n=957) and with an increased number of HDL particles of smaller size (P=3.4x10(-17)) in a fourth study (n=3375). In a combination of 5 cardiovascular disease case-control studies (n=4658 cases and 11 459 controls), a higher gene score was associated with a lower cardiovascular disease risk (per-allele odds ratio, 0.94; 95% confidence interval, 0.90 to 0.98; P=1.2x10(-3); odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; P=1.0x10(-3)).
  
  
  CONCLUSIONS
  A gene score based on 2 PLTP single nucleotide polymorphisms is associated with lower PLTP transcription and activity, an increased number of HDL particles, smaller HDL size, and decreased risk of cardiovascular disease. These findings indicate that PLTP is a proatherogenic entity and suggest that modulation of specific elements of HDL metabolism may offer cardiovascular benefit.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands. m.vergeer@amc.uva.nl
authors.forename: Menno
authors.initials: M
authors.lastname: Vergeer
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Sally L
authors.initials: SL
authors.lastname: Ricketts
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.forename: Karin
authors.initials: K
authors.lastname: Leander
authors.forename: Bruna
authors.initials: B
authors.lastname: Gigante
authors.forename: Maryam
authors.initials: M
authors.lastname: Kavousi
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Ellen
authors.initials: E
authors.lastname: van der Schoot
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Robin P F
authors.initials: RP
authors.lastname: Dullaart
authors.forename: Arie
authors.initials: A
authors.lastname: van Tol
authors.forename: Mieke D
authors.initials: MD
authors.lastname: Trip
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010316:Particle Size; D049294:Phospholipid Transfer Proteins / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors
chemical_list: D005819:Genetic Markers; D008075:Lipoproteins, HDL; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins