Mean age at entry was 59 years (SD 10), 89% of participants were of European descent, and 44% were women. Minor allele frequencies ranged from 0.06 to 0.33 for the principal single nucleotide polymorphisms. For any given polymorphism, minor allele frequencies were similar across studies. Mean baseline concentrations of C reactive protein varied across studies, though standard deviations were broadly similar (see fig B in appendix 3 on bmj.com), with an overall median of 1.7 (5th, 95th centile 0.3, 12.7) mg/L. The regression dilution ratio of ln C reactive protein, adjusted for age and sex, was 0.57 (95% confidence interval 0.51 to 0.64), similar to those observed here for systolic blood pressure (0.51, 0.48 to 0.54), and total cholesterol (0.55, 0.52 to 0.60).
CRP variants, C reactive protein concentration, and levels of other risk factors
Each of these CRP variants was associated with baseline C reactive protein, with per allele differences in C reactive protein concentration of 23% (95% confidence interval 19% to 27%) for rs3093077, 19% (17% to 21%) for rs1205, 14% (12% to 16%) for rs1130864, and 30% (26% to 34%) for rs1800947 (P<0.001; fig 1) (see also fig C in appendix 3 and table F in appendix 1 on bmj.com). These associations were consistent over multiple repeat measures of circulating C reactive protein taken several years apart (see fig D in appendix 3 on bmj.com). With the exception of ethnicity (with which the principal variants were strongly correlated; P<0.001), single genetic variants associated with C reactive protein were not associated with conventional risk factors or other inflammatory markers (fig 1). With haplotype 1 as a reference, CRP haplotypes were associated with differences in ln C reactive protein concentration ranging from 0.1 to 0.34 mg/L and were not associated with conventional risk factors and other characteristics (see figs E-G in appendix 3 and table F in appendix 1 on bmj.com). By contrast, baseline C reactive protein concentration itself was associated with conventional risk factors, inflammatory markers, and other characteristics (see table G in appendix 1 on bmj.com).
Fig 1 Associations of four principal single nucleotide polymorphisms (SNP) related to C reactive protein with various characteristics in individuals free from known coronary heart disease at time of measurement. Estimates presented are based on random (more ...)
Risk ratios for coronary heart disease with CRP genetic variants
Risk ratios for coronary heart disease per addition of a risk (“C reactive protein raising”) allele were 0.93 (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 (fig 2). There was modest heterogeneity in these estimates (I2 values for those risk ratios were 0%, 26%, 0%, and 0%, respectively, see fig C in appendix 3 on bmj.com) with similar findings under a range of circumstances (see table H in appendix 1 on bmj.com). For haplotype analyses, risk ratios for coronary heart disease per copy of haplotype (relative to two copies of haplotype 1) were 1.01 (0.97 to 1.04) with haplotype 2, 0.98 (0.92 to 1.03) with haplotype 3, 0.99 (0.96 to 1.03) with haplotype 4, and 0.98 (0.91 to 1.05) with haplotype 5 (fig 3) (see also fig F in appendix 3 on bmj.com). There was little heterogeneity in these risk ratios (see fig G in appendix 3 on bmj.com). Data were insufficient to investigate effects in different ethnic groups.
Fig 2 Estimates of association of each single nucleotide polymorphism with ln concentrations of C reactive protein and risk of coronary heart disease (CHD). *Frequency of allele for increased concentrations of circulating ln C reactive protein (that is, (more ...)
Fig 3 Estimates of association of each haplotype with ln concentrations of CRP and risk of coronary heart disease. *Based on seven haplotypes and therefore do not add up to 1. Haplotypes 6 and 7 excluded because they represent individuals for whom it (more ...)
Risk ratios for coronary heart disease with usual concentrations of C reactive protein
In analyses restricted to 27 long term prospective studies comprising 124
931 participants and 10
981 incident cases of coronary heart disease, there was an approximately log linear association between C reactive protein concentration and risk of coronary heart disease (see fig H in appendix 3 on bmj.com). In these studies, the risk ratio for coronary heart disease, adjusted for age, sex, and ethnicity only, was 1.49 (1.40 to 1.59) per 1 SD higher “usual” ln C reactive protein concentration (that is, a risk ratio that has made allowance for regression dilution) (fig 4). The risk ratio for coronary heart disease was 1.33 (1.23 to 1.43) after further adjustment for smoking status, history of diabetes mellitus, and usual levels of systolic blood pressure, body mass index (BMI), non-high density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations. There was little evidence of heterogeneity (see fig I in appendix 3 on bmj.com). Risk ratios with higher C reactive protein concentration were broadly similar under a range of circumstances (see fig J in appendix 3 on bmj.com). Multivariable adjusted risk ratios for coronary heart disease with C reactive protein concentration weakened after further adjustment for fibrinogen or interleukin 6 (see table I in appendix 1 on bmj.com).
Fig 4 Estimates of association of circulating concentrations and genetically raised concentrations of C reactive protein (CRP) with risk of coronary heart disease (CHD). *Corrected for regression dilution in C reactive protein and potential confounding (more ...)
Integration of data on CRP variants and C reactive protein concentration
Risk ratios for coronary heart disease were 1.00 (0.90 to 1.13) per 1 SD higher genetically raised C reactive protein as determined by all four principal single nucleotide polymorphisms (163
174 participants, 37
736 cases, 44 studies). This corresponds to a risk ratio of 1.00 (0.97 to 1.02) per 20% lower C reactive protein, which is equivalent to about 0.38 mg/L lower C reactive protein when the population mean is 1.88 mg/L. From information on all common CRP
haplotypes in populations of European descent, the risk ratio was 1.00 (0.89 to 1.12; 152
678 participants, 33
589 cases, 39 studies; fig 4) (see also fig K in appendix 3 on bmj.com).
We observed qualitatively similar results to those reported above in analyses that used different genetic models (see fig L in appendix 3 on bmj.com); excluded variants or studies that deviated from Hardy-Weinberg equilibrium or were judged to be insufficiently strong genetic instruments25
; used fixed effect meta-analysis models (see figs C, G, I, and K in appendix 3 on bmj.com); omitted the 11
734 participants who reported using cardiovascular drugs (including statins) at baseline; omitted the 18
198 participants in clinical trials; included only people of European descent (see fig M in appendix 3 on bmj.com); compared prospective and retrospective studies (fig K in appendix 3 on bmj.com); and compared larger studies versus smaller studies (available on request).