title: The association of C-reactive protein and CRP genotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants.
abstract: BACKGROUND
  It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association.
  
  
  RESULTS
  We estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N = 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95%CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I(2) = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I(2)<7.5%, p>0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80).
  
  
  CONCLUSIONS
  We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.
authors: MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom. d.a.lawlor@bristol.ac.uk
authors: Debbie A
authors: DA
authors: Lawlor
authors: Roger M
authors: RM
authors: Harbord
authors: Nic J
authors: NJ
authors: Timpson
authors: Gordon D O
authors: GD
authors: Lowe
authors: Ann
authors: A
authors: Rumley
authors: Tom R
authors: TR
authors: Gaunt
authors: Ian
authors: I
authors: Baker
authors: John W G
authors: JW
authors: Yarnell
authors: Mika
authors: M
authors: Kivimäki
authors: Meena
authors: M
authors: Kumari
authors: Paul E
authors: PE
authors: Norman
authors: Konrad
authors: K
authors: Jamrozik
authors: Graeme J
authors: GJ
authors: Hankey
authors: Osvaldo P
authors: OP
authors: Almeida
authors: Leon
authors: L
authors: Flicker
authors: Nicole
authors: N
authors: Warrington
authors: Michael G
authors: MG
authors: Marmot
authors: Yoav
authors: Y
authors: Ben-Shlomo
authors: Lyle J
authors: LJ
authors: Palmer
authors: Ian N M
authors: IN
authors: Day
authors: Shah
authors: S
authors: Ebrahim
authors: George Davey
authors: GD
authors: Smith
mesh_terms: D000368:Aged; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism*; D015986:Confounding Factors, Epidemiologic; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies
chemical_list: D002097:C-Reactive Protein