BACKGROUND:Circulating C-reactive protein (CRP) is associated with the metabolic syndrome and might be causally linked to it. Our aim was to generate estimates of the association between plasma CRP and metabolic syndrome phenotypes that were free from confounding and reverse causation, to assess the causal role of this protein.METHODS:We examined associations between serum CRP concentration and metabolic syndrome phenotypes in the British Women's Heart and Health Study. We then compared these estimates with those derived from a mendelian randomised framework with common CRP gene haplotypes to generate unconfounded and unbiased estimates of any causal associations.FINDINGS:In a sample of British women, body-mass index (BMI), systolic blood pressure, waist-to-hip ratio, serum concentrations of HDL cholesterol and triglycerides, and insulin resistance were all associated with plasma CRP concentration. CRP haplotypes were associated with plasma CRP concentration (p<0.0001). With instrumental variable analyses, there was no association between plasma CRP concentration and any of the metabolic syndrome phenotypes analysed. There was strong evidence that linear regression and mendelian randomisation based estimation gave conflicting results for the CRP-BMI association (p=0.0002), and some evidence of conflicting results for the association of CRP with the score for insulin resistance (p=0.0139), triglycerides (p=0.0313), and HDL cholesterol (p=0.0688).INTERPRETATION:Disparity between estimates of the association between plasma CRP and phenotypes comprising the metabolic syndrome derived from conventional analyses and those from a mendelian randomisation approach suggests that there is no causal association between CRP and the metabolic syndrome phenotypes.

SummaryA cross sectional and prospective analysis of 3,745 British women aged 60–79 years at baseline was undertaken. Among these women there were 570 prevalent cases of coronary heart disease (CHD) and 151 new cases among 12,641 person-years of follow up of women who were free of CHD at baseline. Both fibrinogen and CRP were associated with indicators of socioeconomic position in childhood and adulthood and there was a cumulative effect of socioeconomic position from across the life course. The age-adjusted odds ratio (95% confidence interval) of prevalent CHD for a 1 unit (1 g/L) increase in fibrinogen was 1.29 (1.12, 1.49); with full adjustment for all potential confounding factors this attenuated to 1.09 (0.93, 1.28). The hazards ratio for incident CHD among those free of disease at baseline was 1.28 (1.00, 1.64); with full adjustment for all potential confounding factors this attenuated to 1.09 (0.84, 1.44). Similar effects of adjustment for confounding factors were seen for the associations between CRP and both prevalent and incident CHD. By contrast, the strong positive association between smoking (an established causal risk factor for CHD) and CHD was not attenuated by adjustment for life course socioeconomic position or other risk factors. We conclude that fibrinogen and CRP predict CHD but may not be causally related to it.

BACKGROUND:C-reactive protein (CRP) has repeatedly been associated with blood pressure and prevalent and incident hypertension, but whether a causal link exists is uncertain.METHODS AND RESULTS:We assessed the cross-sectional relations of CRP to systolic blood pressure, pulse pressure, and prevalent hypertension in a representative sample of >3500 British women aged 60 to 79 years. For both outcomes, substantial associations were observed. However, these associations were greatly attenuated by adjustment for a wide range of confounding factors acting over the life course. We further investigated causality using a Mendelian randomization approach by examining the association of the 1059G/C polymorphism in the human CRP gene with CRP and with blood pressure, pulse pressure, and hypertension. The polymorphism was associated with a robust difference in CRP, and the expectation would be for higher blood pressure and pulse pressure and greater prevalence of hypertension among those carrying the genetic variant associated with higher CRP levels. This was not observed, and the predicted causal effects of CRP on blood pressure, pulse pressure, and hypertension using instrumental variables methods were close to 0, although with wide CIs.CONCLUSIONS:CRP levels are associated with blood pressure, pulse pressure, and hypertension, but adjustment for life course confounding and a Mendelian randomization approach suggest the elevated CRP levels do not lead to elevated blood pressure.

BACKGROUND:C-reactive protein is an inflammatory marker believed to be of value in the prediction of coronary events. We report data from a large study of C-reactive protein and other circulating inflammatory markers, as well as updated meta-analyses, to evaluate their relevance to the prediction of coronary heart disease.METHODS:Measurements were made in samples obtained at base line from up to 2459 patients who had a nonfatal myocardial infarction or died of coronary heart disease during the study and from up to 3969 controls without a coronary heart disease event in the Reykjavik prospective study of 18,569 participants. Measurements were made in paired samples obtained an average of 12 years apart from 379 of these participants in order to quantify within-person fluctuations in inflammatory marker levels.RESULTS:The long-term stability of C-reactive protein values (within-person correlation coefficient, 0.59; 95 percent confidence interval, 0.52 to 0.66) was similar to that of both blood pressure and total serum cholesterol. After adjustment for base-line values for established risk factors, the odds ratio for coronary heart disease was 1.45 (95 percent confidence interval, 1.25 to 1.68) in a comparison of participants in the top third of the group with respect to base-line C-reactive protein values with those in the bottom third, and similar overall findings were observed in an updated meta-analysis involving a total of 7068 patients with coronary heart disease. By comparison, the odds ratios in the Reykjavik Study for coronary heart disease were somewhat weaker for the erythrocyte sedimentation rate (1.30; 95 percent confidence interval, 1.13 to 1.51) and the von Willebrand factor concentration (1.11; 95 percent confidence interval, 0.97 to 1.27) but generally stronger for established risk factors, such as an increased total cholesterol concentration (2.35; 95 percent confidence interval, 2.03 to 2.74) and cigarette smoking (1.87; 95 percent confidence interval, 1.62 to 2.16).CONCLUSIONS:C-reactive protein is a relatively moderate predictor of coronary heart disease. Recommendations regarding its use in predicting the likelihood of coronary heart disease may need to be reviewed.

Objective— C-reactive protein (CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. Methods and Results— CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft (CABG) patients. Two novel polymorphisms were identified in the CRP gene, −717G>A in the promoter and +1444C>T in the 3′UTR. Among army recruits, CRP was higher in +1444TT homozygotes than +1444 C-allele carriers at baseline (1.04±0.38 versus 0.55±0.06, P =0.014) and at all time points after exercise (2.35±0.68 versus 1.07±0.12, 2.11±0.53 versus 0.88±0.09, and 1.77±0.44 versus 0.71±0.09, P =0.034, P =0.007, and P =0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP (mg/L) rose from 1.97±0.36 at baseline to 167.2±5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post-CABG CRP levels were higher in +1444TT homozygotes compared with +1444C-allele carriers (198±17 versus 164±5, P =0.03). Conclusions— The CRP gene +1444C>T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.

C-reactive protein (CRP), the classic marker of acute-phase response, is an indicator of a variety of pathologic processes, including infections, tissue damage, and chronic inflammatory diseases (1)(2). The majority of more than 15 well-conducted prospective studies in initially healthy individuals have shown a strong and independent association between concentrations of CRP within the reference interval (<5 mg/L) and future major cardiovascular events (3), although in some of them, no such association could be established (4)(5)(6)(7). The summary estimate of the relative risk in formal metaanalysis was 2.0 (95% confidence interval, 1.6–2.5) (3). Furthermore, CRP has been shown to add to risk prediction beyond and above established cardiovascular risk factors (8). On the basis of data from the Physicians’ Health Study and the Nurses’ Health Study, an algorithm for risk assessment of future coronary events that combines both CRP concentration and the ratio of total cholesterol to HDL-cholesterol has recently been proposed (9). Because atherosclerosis represents a low-grade inflammatory process in the vascular bed, high-sensitivity (hs) assays are needed when using circulating CRP concentrations for risk prediction in cardiovascular diseases. Such assays have been developed and are now commercially available (10)(11). However, before screening of individuals at risk can be recommended, CRP distributions in apparently healthy adults in the general population must be known. Such information is scarce. Furthermore, in previous reports, women using oral contraceptives or receiving hormone replacement therapy (HRT), both of which have been shown to significantly increase CRP concentrations, had not been excluded (12)(13)(14)(15). In this report, we describe the frequency distribution of CRP concentrations in 13 527 adult men and women from different representative populations in Western Europe. Furthermore, for one area [the MONICA (Monitoring Trends and Determinants in …

Background: Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events.Methods: A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-associated phospholipase A(2), C-reactive protein, and fibrinogen levels and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles.Results: Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of lipoprotein-associated phospholipase A(2) (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile.Conclusions: Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A(2) appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk. (N Engl J Med 2000;343:1148-55.) (C) 2000 Massachusetts Medical Society.

Data from 342 men who are participants in the Caerphilly Collaborative Heart Disease Study were used to replicate a previous report of a significant relationship between measures of whole-blood viscosity and hearing levels in persons with sensorineural hearing impairment. In the unselected data, there were significant relationships between measures of whole-blood viscosity at high shear rates and hearing threshold levels at 2000 and 4000 Hz, even after accounting for the effects of age and socioeconomic group. In a subset of the data containing 124 persons selected on the basis of likely sensorineural hearing impairment, there were significant relationships between whole-blood viscosity and hearing level at all frequencies, with stronger effects at the higher frequencies. The data support the contention of a potentially important relationship between whole-blood viscosity and sensorineural hearing impairment.