title: Common single nucleotide polymorphisms at the NPC1L1 gene locus significantly predict cardiovascular risk in coronary patients.
abstract: BACKGROUND
  Niemann-Pick C1-like 1 (NPC1L1) is involved in dietary cholesterol absorption and is the direct molecular target of the LDL-lowering drug ezetimibe. Recently, genetic variants in NPC1L1 have been associated with the incidence of cardiovascular events, but it remains unclear if the impact of NPC1L1 on cardiovascular risk is dependent on its role in cholesterol absorption. Furthermore, no direct association of genetic variants in NPC1L1 with coronary atherosclerosis has been established.
  
  
  METHODS
  To further address these issues, we determined the impact of 34 single nucleotide polymorphisms (SNPs) at the NPC1L1 gene locus on the presence of coronary atherosclerosis and prospectively on future cardiovascular events in a cohort of 984 angiographied Caucasian patients.
  
  
  RESULTS
  Out of investigated SNPs, 24 variants were significantly associated with future cardiovascular events. The highest impact was observed for rs55837134 (sex-and age adjusted additive HR = 1.67 [1.28-2.18]; p = 1.3 e-4). Regression analysis conditioned on rs55837134 showed that significant associations between remaining SNPs at the NPC1L1 locus and vascular events did not persist suggesting their dependence on rs55837134. Its significant association remained almost unchanged after further adjustment for total cholesterol, LDL cholesterol, and other cardiovascular risk factors (additive HR = 1.67 [1.28-2.18]; p = 1.7 e-4). In addition, no significant association of investigated NPC1L1 variants with coronary atherosclerosis could be observed, at least after false discovery rate correction.
  
  
  CONCLUSIONS
  Genetic variants of NPC1L1, particularly rs55837134, show a predictive impact on cardiovascular events. Further studies to determine the molecular consequences of common genetic variants in NPC1L1 are needed.
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
authors.forename: Axel
authors.initials: A
authors.lastname: Muendlein
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Medical Central Laboratories, Feldkirch, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leiherer
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Saely
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Rein
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zanolin
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
authors.forename: Elena
authors.initials: E
authors.lastname: Kinz
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Brandtner
authors.affiliation: Medical Central Laboratories, Feldkirch, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Fraunberger
authors.affiliation: Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; Drexel University College of Medicine, Philadelphia, PA, USA. Electronic address: vivit@lkhf.at.
authors.forename: Heinz
authors.initials: H
authors.lastname: Drexel
mesh_terms: D000368:Aged; D001317:Austria / Q000453:epidemiology; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human
keywords: Cardiovascular risk; Cholesterol; Coronary artery disease; NPC1L1; Single nucleotide polymorphisms