title: Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data.
abstract: OBJECTIVE
  To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease.
  
  
  METHODS
  Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries.
  
  
  METHODS
  194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors.
  
  
  METHODS
  Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals.
  
  
  RESULTS
  CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference).
  
  
  CONCLUSIONS
  Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
authors.forename: Frances
authors.initials: F
authors.lastname: Wensley
authors.forename: Pei
authors.initials: P
authors.lastname: Gao
authors.forename: Stephen
authors.initials: S
authors.lastname: Burgess
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaptoge
authors.forename: Emanuele
authors.initials: E
authors.lastname: Di Angelantonio
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: George
authors.initials: G
authors.lastname: Davey-Smith
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Manjinder
authors.initials: M
authors.lastname: Sandhu
authors.forename: Sonia
authors.initials: S
authors.lastname: Anand
authors.forename: Mark B
authors.initials: MB
authors.lastname: Pepys
authors.forename: Liam
authors.initials: L
authors.lastname: Smeeth
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Casas
authors.forename: Simon G
authors.initials: SG
authors.lastname: Thompson
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: John
authors.initials: J
authors.lastname: Danesh
mesh_terms: D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D002097:C-Reactive Protein