title: Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.
abstract: BACKGROUND
  Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.
  
  
  OBJECTIVE
  To investigate association of genetic loci with CRP levels and risk of coronary heart disease.
  
  
  METHODS
  We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.
  
  
  METHODS
  Risk of coronary heart disease.
  
  
  RESULTS
  Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.
  
  
  CONCLUSIONS
  The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.
authors: Faculty of Medicine, Imperial College London, London, United Kingdom. p.elliott@imperial.ac.uk
authors: Paul
authors: P
authors: Elliott
authors: John C
authors: JC
authors: Chambers
authors: Weihua
authors: W
authors: Zhang
authors: Robert
authors: R
authors: Clarke
authors: Jemma C
authors: JC
authors: Hopewell
authors: John F
authors: JF
authors: Peden
authors: Jeanette
authors: J
authors: Erdmann
authors: Peter
authors: P
authors: Braund
authors: James C
authors: JC
authors: Engert
authors: Derrick
authors: D
authors: Bennett
authors: Lachlan
authors: L
authors: Coin
authors: Deborah
authors: D
authors: Ashby
authors: Ioanna
authors: I
authors: Tzoulaki
authors: Ian J
authors: IJ
authors: Brown
authors: Shahrul
authors: S
authors: Mt-Isa
authors: Mark I
authors: MI
authors: McCarthy
authors: Leena
authors: L
authors: Peltonen
authors: Nelson B
authors: NB
authors: Freimer
authors: Martin
authors: M
authors: Farrall
authors: Aimo
authors: A
authors: Ruokonen
authors: Anders
authors: A
authors: Hamsten
authors: Noha
authors: N
authors: Lim
authors: Philippe
authors: P
authors: Froguel
authors: Dawn M
authors: DM
authors: Waterworth
authors: Peter
authors: P
authors: Vollenweider
authors: Gerard
authors: G
authors: Waeber
authors: Marjo-Riitta
authors: MR
authors: Jarvelin
authors: Vincent
authors: V
authors: Mooser
authors: James
authors: J
authors: Scott
authors: Alistair S
authors: AS
authors: Hall
authors: Heribert
authors: H
authors: Schunkert
authors: Sonia S
authors: SS
authors: Anand
authors: Rory
authors: R
authors: Collins
authors: Nilesh J
authors: NJ
authors: Samani
authors: Hugh
authors: H
authors: Watkins
authors: Jaspal S
authors: JS
authors: Kooner
mesh_terms: D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D003327:Coronary Disease / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D002097:C-Reactive Protein