title: Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.
abstract: BACKGROUND
  Rare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD.
  
  
  METHODS
  Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals.
  
  
  RESULTS
  Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13-0.24] mmol/L, p = 1.5x10(-10)). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76-0.89], p = 2.1x10(-7)). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD.
  
  
  CONCLUSIONS
  A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.
authors: Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany.
authors: Patrick
authors: P
authors: Linsel-Nitschke
authors: Anika
authors: A
authors: Götz
authors: Jeanette
authors: J
authors: Erdmann
authors: Ingrid
authors: I
authors: Braenne
authors: Peter
authors: P
authors: Braund
authors: Christian
authors: C
authors: Hengstenberg
authors: Klaus
authors: K
authors: Stark
authors: Marcus
authors: M
authors: Fischer
authors: Stefan
authors: S
authors: Schreiber
authors: Nour Eddine
authors: NE
authors: El Mokhtari
authors: Arne
authors: A
authors: Schaefer
authors: Jürgen
authors: J
authors: Schrezenmeir
authors: Jürgen
authors: J
authors: Schrezenmeier
authors: Diana
authors: D
authors: Rubin
authors: Anke
authors: A
authors: Hinney
authors: Thomas
authors: T
authors: Reinehr
authors: Christian
authors: C
authors: Roth
authors: Jan
authors: J
authors: Ortlepp
authors: Peter
authors: P
authors: Hanrath
authors: Alistair S
authors: AS
authors: Hall
authors: Massimo
authors: M
authors: Mangino
authors: Wolfgang
authors: W
authors: Lieb
authors: Claudia
authors: C
authors: Lamina
authors: Iris M
authors: IM
authors: Heid
authors: Angela
authors: A
authors: Doering
authors: Christian
authors: C
authors: Gieger
authors: Annette
authors: A
authors: Peters
authors: Thomas
authors: T
authors: Meitinger
authors: H-Erich
authors: HE
authors: Wichmann
authors: Inke R
authors: IR
authors: König
authors: Andreas
authors: A
authors: Ziegler
authors: Florian
authors: F
authors: Kronenberg
authors: Nilesh J
authors: NJ
authors: Samani
authors: Heribert
authors: H
authors: Schunkert
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D003327:Coronary Disease / Q000235:genetics* / Q000517:prevention & control*; D014644:Genetic Variation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D011973:Receptors, LDL / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D011973:Receptors, LDL