August 19, 2008Open Access
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
Key Result
The CRP genetic variant rs1130864 TT genotype was not associated with coronary heart disease compared to the CT/CC genotype (OR 1.01), suggesting no causal association between circulating CRP and CHD risk.
Study Design
Type
Meta-Analysis (n=18,637)
Multicenter
Yes
Structured PICO
Does the CRP genetic variant +1444C>T (rs1130864), which affects circulating CRP levels, increase the risk of coronary heart disease?
P
Population
18,637 participants from 5 pooled studies, including 4,610 cases of coronary heart disease (CHD).
I
Intervention
CRP genetic variant +1444C>T (rs1130864) and circulating CRP levels
C
Comparator
CT/CC genotype (compared to TT genotype) or per additional T allele
O
Outcome
Coronary heart disease (CHD) riskhard clinical
Mendelian randomization analysis using the CRP genetic variant +1444C>T does not support a causal association between circulating CRP levels and coronary heart disease risk.
Main Result
Effect estimate: OR 1.01 (95% CI 0.88-1.16)
Limitations
- The genetic variant explains less than 1% of the variation in CRP levels, resulting in wide confidence intervals for the instrumental variables analysis
- Very large, extended genetic association studies would be required to completely rule out a causal association
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. METHODS AND 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)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.