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.
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.
Lawlor
Debbie A
DA
MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom. d.a.lawlor@bristol.ac.uk
Harbord
Roger M
RM
Timpson
Nic J
NJ
Lowe
Gordon D O
GD
Rumley
Ann
A
Gaunt
Tom R
TR
Baker
Ian
I
Yarnell
John W G
JW
Kivimäki
Mika
M
Kumari
Meena
M
Norman
Paul E
PE
Jamrozik
Konrad
K
Hankey
Graeme J
GJ
Almeida
Osvaldo P
OP
Flicker
Leon
L
Warrington
Nicole
N
Marmot
Michael G
MG
Ben-Shlomo
Yoav
Y
Palmer
Lyle J
LJ
Day
Ian N M
IN
Ebrahim
Shah
S
Smith
George Davey
GD
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
D002097:C-Reactive Protein