title: Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
abstract: BACKGROUND
  An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood.
  
  
  METHODS
  We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects.
  
  
  RESULTS
  Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished.
  
  
  CONCLUSIONS
  We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.
authors.affiliation: Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: John F
authors.initials: JF
authors.lastname: Peden
authors.forename: Jemma C
authors.initials: JC
authors.lastname: Hopewell
authors.forename: Theodosios
authors.initials: T
authors.lastname: Kyriakou
authors.forename: Anuj
authors.initials: A
authors.lastname: Goel
authors.forename: Simon C
authors.initials: SC
authors.lastname: Heath
authors.forename: Sarah
authors.initials: S
authors.lastname: Parish
authors.forename: Simona
authors.initials: S
authors.lastname: Barlera
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Franzosi
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.forename: Derrick
authors.initials: D
authors.lastname: Bennett
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.forename: Anders
authors.initials: A
authors.lastname: Malarstig
authors.forename: Fiona R
authors.initials: FR
authors.lastname: Green
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Bruna
authors.initials: B
authors.lastname: Gigante
authors.forename: Karin
authors.initials: K
authors.lastname: Leander
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.forename: Udo
authors.initials: U
authors.lastname: Seedorf
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Rory
authors.initials: R
authors.lastname: Collins
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
mesh_terms: D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D018082:Kringles / Q000235:genetics; D016013:Likelihood Functions; D017270:Lipoprotein(a) / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D009203:Myocardial Infarction / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012307:Risk Factors
chemical_list: D005819:Genetic Markers; D017270:Lipoprotein(a)