Original Article
Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease
N Engl J Med 2008; 359:1897-1908October 30, 2008
- Abstract
Background
Elevated levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested whether this is a causal association.
Methods
We studied 10,276 persons from a general population cohort, including 1786 in whom ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed. We examined another 31,992 persons from a cross-sectional general population study, of whom 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease. Finally, we compared 2238 patients with ischemic heart disease with 4474 control subjects and 612 patients with ischemic cerebrovascular disease with 1224 control subjects. We measured levels of high-sensitivity CRP and conducted genotyping for four CRP polymorphisms and two apolipoprotein E polymorphisms.
Results
The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the four CRP polymorphisms were associated with an increase in CRP levels of up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, apolipoprotein E genotypes were associated with both elevated cholesterol levels and an increased risk of ischemic heart disease.
Conclusions
Polymorphisms in the CRP gene are associated with marked increases in CRP levels and thus with a theoretically predicted increase in the risk of ischemic vascular disease. However, these polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease.
Media in This Article
Figure 1
Risk of Ischemic Heart Disease (Panel A) and Ischemic Cerebrovascular Disease (Panel B) as a Function of Plasma Levels of C-Reactive Protein (CRP) in the General Population.Figure 2
Plasma Levels of C-Reactive Protein (CRP) as a Function of CRP Genotype and Genotype Combination in the General Population.Article Activity
- Article
Elevated plasma levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease.1-5 However, whether CRP is simply a marker for ischemic vascular disease or whether elevated CRP levels actually contribute directly to causing such disorders is presently unknown. This question has clinical importance, since several drugs that specifically lower CRP levels are being developed,6 with the ultimate aim of preventing ischemic vascular disease.
The random assortment of genes that occurs during gamete formation provides a relatively unbiased method of assessing whether risk factors that have a genetic component are in fact causally related to clinical outcomes.7 This phenomenon has sometimes been termed “mendelian randomization.” Thus, genetic variants that specifically increase plasma levels of CRP8,9 provide an ideal system to assess the consequences of lifelong high CRP levels, independently of other risk factors.7
We examined the hypothesis that genetically elevated CRP levels cause increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested, first, whether CRP levels were associated with the risks of ischemic heart disease and ischemic cerebrovascular disease; second, whether CRP single-nucleotide polymorphisms were associated with CRP levels; and third, whether CRP polymorphisms were associated with increases in the risks of ischemic heart disease and ischemic cerebrovascular disease that were consistent with their effects on CRP levels.
Methods
We studied four independent cohorts of white people of Danish descent. These groups were defined so that no person appears in more than one of the four analysis groups, thus permitting independent confirmation of the findings in each group. Details about each study cohort are provided in the Supplementary Appendix, available with the full text of this article at www.nejm.org.
The studies were approved by Herlev Hospital and by Danish ethics committees (the Copenhagen and Frederiksberg committee and the Copenhagen County committee) and were conducted according to the standards of the Declaration of Helsinki. Written informed consent was obtained from the participants.
Study Cohorts
The Copenhagen City Heart Study10,11 is a prospective study of a cohort of persons randomly selected from the population of the city of Copenhagen. Data were available from this study on rates of ischemic heart disease (including fatal or nonfatal myocardial infarction, symptoms of angina pectoris, and revascularization procedures) and rates of ischemic cerebrovascular disease (including fatal or nonfatal ischemic stroke, transient ischemic attack, and amaurosis fugax). We included 10,276 participants from this study in the present analysis, including 1786 in whom ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed.
The Copenhagen General Population Study10,12 is a cross-sectional study of persons selected from the population of the city of Copenhagen. Diagnoses of ischemic heart disease and ischemic cerebrovascular disease were made according to the same criteria as those used in the Copenhagen City Heart Study. We included 37,690 participants in this study in the present analysis. Of these, 31,992 participants (of whom 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease) were analyzed as a single cohort for the association of CRP polymorphisms with clinical events; 4474 additional participants were used as controls for the Copenhagen Ischemic Heart Disease Study, and 1224 were used as controls for the Copenhagen Carotid Stroke Study. Of the 37,690 participants, 34,233 who were not receiving statin treatment were included in the analysis of correlation between CRP polymorphisms and plasma CRP levels.
The Copenhagen Ischemic Heart Disease Study12 was conducted on a cohort of 2238 patients who had been referred for coronary angiography and had documented evidence of ischemic heart disease on the basis of characteristic symptoms of stable angina pectoris, plus at least one of the following: at least one coronary stenosis of more than 50% of vessel diameter or diffuse atherosclerosis according to coronary angiography, a previous myocardial infarction, or a positive result on a bicycle exercise electrocardiography test. These patients were matched according to sex and age (within 1-year strata) with 4474 control subjects without ischemic heart disease from the Copenhagen General Population Study.
The Copenhagen Carotid Stroke Study13 was conducted on a cohort of 612 patients who had been referred for carotid artery ultrasonography and had documented evidence of ischemic cerebrovascular disease on the basis of ischemic stroke, transient ischemic attack, or amaurosis fugax, together with a stenosis of at least 50% of a carotid artery. Patients with hemorrhage were excluded by means of computed tomography. These patients were matched according to sex and age (within 1-year strata) with 1224 control subjects without ischemic cerebrovascular disease from the Copenhagen General Population Study.
Genotyping and Biochemical Analyses
An ABI PRISM 7900HT Sequence Detection System (Applied Biosystems) was used to perform genotyping for four single-nucleotide polymorphisms in the CRP gene (rs3091244, rs1130864, rs1205, and rs3093077)8 and two in the apolipoprotein E gene (rs429358 and rs7412).14 Genotyping was verified by DNA sequencing in more than 30 persons with each genotype. High-sensitivity CRP was measured by nephelometry or turbidimetry. CRP levels were classified as low (<1.0 mg per liter), average (1.0 to 3.0 mg per liter), or high (>3.0 mg per liter). Levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured with the use of standard hospital assays (Boehringer Mannheim or Konelab). The level of LDL cholesterol was calculated with the use of the Friedewald equation if the triglyceride level was less than 4 mmol per liter (354 mg per deciliter) and was measured directly for higher triglyceride levels.
Statistical Analysis
We used Stata and NCSS-PASS software for all analyses. For trend tests, the groups of subjects classified according to CRP level, genotype, or genotype combination were coded as 1, 2, 3, and so forth, ranked according to increasing CRP levels. From the four CRP polymorphisms, we generated all possible genotype combinations and ranked the nine most common combinations according to increasing plasma CRP levels. Apolipoprotein E genotypes were ranked in a similar fashion according to increasing plasma cholesterol levels.
To investigate our study hypothesis, we first analyzed the relationship between plasma CRP levels and the risks of ischemic heart disease and ischemic cerebrovascular disease in the prospective Copenhagen City Heart Study, with the use of left truncation (or delayed entry) from the results of examinations conducted from 1991 through 1994.15 Cox regression models with age as the time scale, adjusted for age, sex, and use or nonuse of statins, were used to estimate the hazard ratios for ischemic heart disease and ischemic cerebrovascular disease. Additional regression models that included CRP genotype and multivariable models that included a full set of available risk factors (see Table 1 and Table 2 in the Supplementary Appendix) were also developed. Data from the serial examinations of the Copenhagen City Heart Study were used as time-dependent covariates for multivariable adjustment.
Second, we analyzed the relationship between CRP polymorphisms and polymorphism combinations and plasma CRP levels in the cross-sectional Copenhagen General Population Study. Analyses were performed with the use of Kruskal–Wallis analysis of variance.
Third, we analyzed the relationship between CRP polymorphisms and the risks of ischemic heart disease and ischemic cerebrovascular disease in the prospective Copenhagen City Heart Study, with the use of the results of examinations conducted from 1976 through 1978 that involved left truncation (or delayed entry).15 Cox regression models with age as the time scale, adjusted for age and sex (or adjusted for all covariates), were used to estimate the hazard ratios for ischemic heart disease and ischemic cardiovascular disease. This analysis was retested in the cross-sectional Copenhagen General Population Study; conditional logistic-regression analyses adjusted for age and sex (or for all covariates) were used to estimate the odds ratios for ischemic heart disease and ischemic cerebrovascular disease.
Finally, a third test of the relationship between CRP polymorphisms and the risk of vascular disease was performed, with data from the Copenhagen Ischemic Heart Disease Study used for the ischemic heart disease end point and data from the Copenhagen Carotid Stroke Study used for the ischemic cerebrovascular disease end point. For each of these analyses, patients were matched according to age and sex with control subjects from the Copenhagen General Population Study, and conditional logistic-regression analyses (either crude or adjusted for all covariates) were used to estimate the odds ratios for ischemic heart disease and ischemic cerebrovascular disease.
The increases in the hazard ratios for ischemic heart disease and ischemic cerebrovascular disease for a 1% increase in CRP level in the Copenhagen City Heart Study were used to predict theoretical hazard ratios for ischemic heart disease and ischemic cerebrovascular disease associated with the changes in CRP levels caused by the combined genotypes. Observed and theoretically predicted hazard ratios as a function of plasma CRP levels were corrected for regression dilution bias16,17; similar calculations were performed for apolipoprotein E genotype, plasma cholesterol levels, and the risk of ischemic heart disease. Logistic-regression analysis was used to calculate a combined odds ratio for ischemic heart disease and ischemic cerebrovascular disease as a function of genotype for all studies combined (all patients with ischemic heart disease or ischemic cerebrovascular disease as compared with all control subjects).
Results
Selected clinical characteristics of the participants in each study cohort are shown in Tables 1, 2, and 3 of the Supplementary Appendix. As would be anticipated, persons in both cohorts with vascular disease were older and more likely to be male than those without vascular disease, except for the age- and sex-matched patients and control subjects of the Copenhagen Ischemic Heart Disease Study and the Copenhagen Carotid Stroke Study. Those with vascular disease also tended to have higher levels of total and LDL cholesterol (except for those in the Copenhagen General Population Study, in which persons with vascular disease were more likely to use lipid-lowering therapy) and higher rates of diabetes, cigarette smoking, and use of antihypertensive therapy.
Plasma CRP and the Risk of Vascular Disease
The risk of ischemic heart disease was increased by a factor of 2.2 (95% confidence interval [CI], 1.6 to 2.9) and the risk of ischemic cerebrovascular disease by a factor of 1.6 (95% CI, 1.1 to 2.5) in persons with CRP levels above 3 mg per liter, as compared with persons with CRP levels below 1 mg per liter, after adjustment for age, sex, and use or nonuse of statins (Figure 1Figure 1
Risk of Ischemic Heart Disease (Panel A) and Ischemic Cerebrovascular Disease (Panel B) as a Function of Plasma Levels of C-Reactive Protein (CRP) in the General Population.). After adjustment for age, sex, use or nonuse of statins, and CRP genotype, the corresponding hazard ratios were 2.2 (95% CI, 1.6 to 2.9) and 1.6 (95% CI, 1.1 to 2.5). After multivariate adjustment, the hazard ratios were 1.6 (95% CI, 1.2 to 2.1) and 1.3 (95% CI, 0.8 to 2.0). P for trend was less than 0.001 in all analyses.CRP Polymorphisms and Plasma CRP
For the CRP polymorphism rs1205, the AA genotype was associated with plasma CRP levels that were 23% lower than those associated with the GG genotype (P for trend, <0.001) (Figure 2Figure 2
Plasma Levels of C-Reactive Protein (CRP) as a Function of CRP Genotype and Genotype Combination in the General Population.). Significant differences in plasma CRP levels were also associated with the rs1130864 polymorphism (TT vs. CC genotype, 24% increase), the rs3091244 polymorphism (AA vs. CC genotype, 67% increase), and the rs3093077 polymorphism (GG vs. TT genotype, 53% increase) (P for trend for all polymorphisms, <0.001). Combining the genotypes resulted in a difference of up to 64% in plasma CRP levels between the lowest and highest levels among the most common genotype combinations (Figure 2). Partial r2 values for the different CRP polymorphisms ranged from 0.4 to 2.0%.CRP Polymorphisms and the Risk of Vascular Disease
The various cardiovascular risk factors were equally distributed among the different CRP genotype combinations (see Table 3 in the Supplementary Appendix). This was also true for each of the four genotypes separately and for genotype combinations in each of the individual studies (data not shown).
The hazard ratios for ischemic heart disease and ischemic cerebrovascular disease as a function of genotype in the Copenhagen City Heart Study did not differ from 1.0 for any of the individual CRP polymorphisms or for genotype combinations (P for trend, 0.28 to 0.94) (Figure 3Figure 3
Risk of Ischemic Heart Disease as a Function of C-Reactive Protein (CRP) Genotype and Genotype Combination. and Figure 4Figure 4
Risk of Ischemic Cerebrovascular Disease as a Function of C-Reactive Protein (CRP) Genotype and Genotype Combination.). These findings were confirmed in the Copenhagen General Population Study (P for trend, 0.13 to 0.95), the Copenhagen Ischemic Heart Disease Study (P for trend, 0.53 to 0.97), and the Copenhagen Carotid Stroke Study (P for trend, 0.79 to 0.99).Predicted versus Observed Risk of Vascular Disease
We assumed that if an elevation in CRP level has a causal association with ischemic vascular disease, then genetically elevated plasma CRP levels should confer the same increase in disease risk as that observed for elevated plasma CRP levels encountered in the general population. On the basis of this assumption, we estimated that the 64% increment in plasma CRP levels due to CRP genotype combination would predict increased risks of up to 32% (hazard ratio, 1.32; 95% CI, 1.26 to 1.39) for ischemic heart disease and of up to 25% (hazard ratio, 1.25; 95% CI, 1.15 to 1.35) for ischemic cerebrovascular disease (Figure 5Figure 5
Summary of Studies of the Effect of C-Reactive Protein (CRP) Genotype Combination and Apolipoprotein E Genotype on the Risk of Ischemic Heart Disease (IHD). and Figure 6Figure 6
Summary of Studies of the Effect of C-Reactive Protein (CRP) Genotype Combination on the Risk of Ischemic Cerebrovascular Disease (ICVD).). However, when the data from all studies of ischemic heart disease and ischemic cerebrovascular disease shown in Figure 3 and Figure 4 were combined to achieve the maximal statistical power, the observed odds ratios for ischemic heart disease and ischemic cerebrovascular disease as a function of genotype combination did not differ significantly from 1.0 (Figure 5 and Figure 6). Similar observations were made when genotype combinations 3 to 6 or 7 to 9 were pooled and compared with genotype combination 1.To test the predictive power of our method and to demonstrate that the risk of coronary disease in the study cohorts follows established patterns, we examined the influence of apolipoprotein E genotype on the risk of ischemic heart disease in our study sample. The range of apolipoprotein E genotypes was associated with an increment in plasma cholesterol levels of up to 14%. Given this increment, we predicted hazard ratios for ischemic heart disease of up to 1.12 (95% CI, 1.06 to 1.17) across the range of apolipoprotein E genotypes (Figure 5). When the data from all studies of ischemic heart disease were combined to achieve the maximal statistical power, the observed odds ratio for ischemic heart disease as a function of apolipoprotein E genotype increased with increasing cholesterol levels to 1.35 (95% CI, 1.12 to 1.61) for the highest-risk genotype. We did not perform a similar analysis for ischemic cerebrovascular disease, since a relationship with apolipoprotein E genotype has not been clearly established for this disorder.
Discussion
The principal finding of this study is that CRP polymorphisms are associated with markedly increased CRP levels but not with an increased risk of ischemic heart disease or ischemic cerebrovascular disease. The absence of an increased risk of ischemic vascular disease associated with genetically elevated CRP levels was consistently observed in four large, independent studies, including a prospective study of the general population, a cross-sectional study of the general population, and two case–control studies.
In epidemiologic studies, elevated plasma CRP levels are consistently associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease,1-5 as was confirmed in the present study. However, most8,18-27 but not all8,28-30 previous studies have shown no association between CRP polymorphisms or haplotypes and the risk of ischemic vascular disease. It has therefore been unclear whether CRP is merely a marker of underlying atherosclerosis or is itself a causal factor for atherosclerosis and ischemic vascular disease. The present study, which is substantially larger than previous studies, was able to exclude small increases in the risk of ischemic vascular disease. For example, in our analysis, we described a genotype combination (7 to 9 vs. 1) associated with a 43% increase in CRP level and thus a theoretically predicted risk of ischemic heart disease of 1.21 (95% CI, 1.17 to 1.25). Instead of this elevated risk, however, we observed a risk of 0.87 (95% CI, 0.75 to 1.02), and our analysis had 90% statistical power to exclude an odds ratio for ischemic heart disease of 1.16, thus effectively excluding the predicted association.
Our CRP results are in contrast to our results for apolipoprotein E genotypes and to emerging genetic data31,32 that show that nearly all gene variants that increase LDL cholesterol (8 of 11 alleles32) are also associated with an increased risk of ischemic heart disease. The finding that apolipoprotein E genotype variants were associated with higher odds ratios for ischemic heart disease in our study than would be theoretically predicted on the basis of elevated cholesterol levels alone may be explained by the fact that these genotypes also cause elevated levels of nonfasting triglycerides,14 which are known to increase the risk of ischemic heart disease independently of cholesterol levels.10,33 The CRP genetic data are more like the genetic data for HDL cholesterol. Only a very small fraction of alleles related to HDL cholesterol were associated with the risk of coronary artery disease.12,32
Several limitations of our study should be considered in evaluating our results. It cannot be totally ruled out that the CRP polymorphisms studied are related to higher plasma levels of functionally less active CRP. However, we consider this unlikely, since none of the polymorphisms in our analysis are located in the coding sequence of the CRP gene. The three-allelic CRP promoter polymorphism studied (rs3091244) affects transcription-factor binding and transcriptional activity, which probably leads to increased levels of fully functional CRP.21,34 In addition, the meaning of theoretically predicted hazard ratios as a function of plasma CRP (as shown in Figure 5 and Figure 6) may be somewhat difficult to understand. However, presentation of the data in this form offers a simple way of visualizing the study design, and the oversimplification involved in these predictions does not invalidate the conclusions of the study. Furthermore, our four studies have limitations and potential biases that differ from study to study owing to their different designs, although the results of the four studies were similar. Also, we studied only persons of white race, and therefore our results may not apply to other races or ethnic groups.
A potential limitation of our study is lack of statistical power. We cannot exclude a small but measurable increase in risk associated with CRP genotype. For example, the 95% confidence interval for the comparison of genotype combinations 7 to 9 versus combination 1 was 0.75 to 1.02. This suggests that CRP genotypes may be associated with an increase in risk of up to 2%. However, the CRP genotypes clearly were not associated with increases in the risks of ischemic heart disease and ischemic cerebrovascular disease of the magnitudes that were theoretically predicted by the change in CRP levels.
Finally, the limitations of the study design also need to be considered.35,36 Our study makes use of naturally occurring genetic variation resulting from independent gene assortment, sometimes termed “mendelian randomization,” as the basis for our analyses of association. The principal potential limitation to this method is confounding by variation in nearby genes. If variants of another gene related to the risk of ischemic vascular disease are in linkage disequilibrium with the CRP polymorphisms we have studied, this will confound our analysis. Although such confounding is difficult to exclude completely, it is unlikely that it would explain our finding that CRP genetic variation was associated with elevated CRP levels without predicting an increased risk of ischemic vascular disease. For example, one could assume that elevated CRP levels in fact cause ischemic vascular disease but that this relationship is obscured in our analysis by confounding. For this to be true, all CRP variants examined in this study would have to be in linkage disequilibrium with another gene that, independently of plasma CRP levels, decreases the risk of ischemic vascular disease to the same extent that plasma CRP increases the risk. Such a circumstance is unlikely. Furthermore, according to the HapMap database, linkage disequilibrium is not detected between the CRP polymorphisms used in our study and other known nearby genes.
In conclusion, we show that genetic variants that are associated with lifelong increases in plasma CRP levels are not associated with an increased risk of ischemic heart disease or ischemic cerebrovascular disease. This finding suggests that the increase in the risk of ischemic vascular disease associated with higher plasma CRP levels observed in epidemiologic studies may not be causal, but rather that increased CRP levels are simply a marker for atherosclerosis and ischemic vascular disease.
Supported by the Danish Heart Foundation.
Dr. Nordestgaard reports receiving consulting fees from BG Medicine and AstraZeneca and lecture fees from AstraZeneca, Sanofi-Aventis, Merck, Pfizer, and Boehringer Ingelheim; Dr. Sillesen, consulting fees from Merck, Pfizer, BG Medicine, Boehringer Ingelheim, Sanofi-Aventis, and AstraZeneca; Dr. Grande, consulting fees from AstraZeneca; and Dr. Tybjærg-Hansen, lecture fees from Pfizer and Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
We thank Hanne Damm, Dorthe Uldall Andersen, and Dorthe Kjeldgaard Hansen for their assistance with the large-scale genotyping and the staff and participants of the Copenhagen City Heart Study, the Copenhagen General Population Study, the Copenhagen Ischemic Heart Disese Study, and the Copenhagen Carotid Stroke Study for their important contributions to our study.
Source Information
From the Department of Clinical Biochemistry (J.Z., B.G.N.) and the Copenhagen General Population Study (J.Z., A.T.-H., J.S.J., B.G.N.), Herlev Hospital; the Departments of Clinical Biochemistry (A.T.-H.), Cardiology (P.G.), and Vascular Surgery (H.S.), Rigshospitalet; the Copenhagen City Heart Study, Bispebjerg Hospital (A.T.-H., J.S.J., B.G.N.); and the Department of Cardiology, Gentofte Hospital (J.S.J.) — all at Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen.
Address reprint requests to Dr. Nordestgaard at the Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark, or at brno@heh.regionh.dk.
- References
References
1
Ridker PM . Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003;107:363-369
CrossRef | Web of Science | Medline2
Danesh J ,Wheeler JG ,Hirschfield GM , et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387-1397
Full Text | Web of Science | Medline3
Everett BM ,Kurth T ,Buring JE ,Ridker PM . The relative strength of C-reactive protein and lipid levels as determinants of ischemic stroke compared with coronary heart disease in women. J Am Coll Cardiol 2006;48:2235-2242
CrossRef | Web of Science | Medline4
Ballantyne CM ,Hoogeveen RC ,Bang H , et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med 2005;165:2479-2484
CrossRef | Web of Science | Medline5
Sattar N ,Murray HM ,McConnachie A , et al. C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Circulation 2007;115:981-989
CrossRef | Web of Science | Medline6
Lowe GD ,Pepys MB . C-reactive protein and cardiovascular disease: weighing the evidence. Curr Atheroscler Rep 2006;8:421-428
CrossRef | Medline7
Smith GD ,Ebrahim S . Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 2004;33:30-42
CrossRef | Web of Science | Medline8
Miller DT ,Zee RY ,Suk DJ , et al. Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet 2005;69:623-638
CrossRef | Web of Science | Medline9
Carlson CS ,Aldred SF ,Lee PK , et al. Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet 2005;77:64-77
CrossRef | Web of Science | Medline10
Nordestgaard BG ,Benn M ,Schnohr P ,Tybjaerg-Hansen A . Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308
CrossRef | Web of Science | Medline11
Schnohr P ,Jensen JS ,Scharling H ,Nordestgaard BG . Coronary heart disease risk factors ranked by importance for the individual and community: a 21 year follow-up of 12 000 men and women from the Copenhagen City Heart Study. Eur Heart J 2002;23:620-626
CrossRef | Web of Science | Medline12
Frikke-Schmidt R ,Nordestgaard BG ,Stene MC , et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 2008;299:2524-2532
CrossRef | Web of Science | Medline13
Agerholm-Larsen B ,Tybjaerg-Hansen A ,Frikke-Schmidt R ,Gronholdt ML ,Jensen G ,Nordestgaard BG . ACE gene polymorphism as a risk factor for ischemic cerebrovascular disease. Ann Intern Med 1997;127:346-355
Web of Science | Medline14
Frikke-Schmidt R ,Tybjaerg-Hansen A ,Steffensen R ,Jensen G ,Nordestgaard BG . Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study. J Am Coll Cardiol 2000;35:1192-1199
CrossRef | Web of Science | Medline15
Refinements of the semiparametric proportional hazards model. In: Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. 2nd ed. New York: Springer-Verlag, 2003:295-325.
16
Clarke R ,Shipley M ,Lewington S , et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 1999;150:341-353
Web of Science | Medline17
MacMahon S ,Peto R ,Cutler J , et al. Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-774
CrossRef | Web of Science | Medline18
Casas JP ,Shah T ,Cooper J , et al. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol 2006;35:922-931
CrossRef | Web of Science | Medline19
Wang Q ,Hunt SC ,Xu Q , et al. Association study of CRP gene polymorphisms with serum CRP level and cardiovascular risk in the NHLBI Family Heart Study. Am J Physiol Heart Circ Physiol 2006;291:H2752-H2757
CrossRef | Web of Science | Medline20
Kardys I ,de Maat MP ,Uitterlinden AG ,Hofman A ,Witteman JC . C-reactive protein gene haplotypes and risk of coronary heart disease: the Rotterdam Study. Eur Heart J 2006;27:1331-1337
CrossRef | Web of Science | Medline21
Kovacs A ,Green F ,Hansson LO , et al. A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein. Atherosclerosis 2005;178:193-198
CrossRef | Web of Science | Medline22
Zee RY ,Ridker PM . Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis. Atherosclerosis 2002;162:217-219
CrossRef | Web of Science | Medline23
Kathiresan S ,Larson MG ,Vasan RS , et al. Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation 2006;113:1415-1423
CrossRef | Web of Science | Medline24
Reitz C ,Berger K ,de Maat MP , et al. CRP gene haplotypes, serum CRP, and cerebral small-vessel disease: the Rotterdam Scan Study and the MEMO Study. Stroke 2007;38:2356-2359
CrossRef | Web of Science | Medline25
Ladenvall C ,Jood K ,Blomstrand C ,Nilsson S ,Jern C ,Ladenvall P . Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype. Stroke 2006;37:2018-2023
CrossRef | Web of Science | Medline26
Flex A ,Gaetani E ,Papaleo P , et al. Proinflammatory genetic profiles in subjects with history of ischemic stroke. Stroke 2004;35:2270-2275
CrossRef | Web of Science | Medline27
Bis JC ,Heckbert SR ,Smith NL , et al. Variation in inflammation-related genes and risk of incident nonfatal myocardial infarction or ischemic stroke. Atherosclerosis 2008;198:166-173
CrossRef | Web of Science | Medline28
Lange LA ,Carlson CS ,Hindorff LA , et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 2006;296:2703-2711
CrossRef | Web of Science | Medline29
Balistreri CR ,Vasto S ,Listi F , et al. Association between +1059G/C CRP polymorphism and acute myocardial infarction in a cohort of patients from Sicily: a pilot study. Ann N Y Acad Sci 2006;1067:276-281
CrossRef | Web of Science | Medline30
Szalai AJ ,Alarcon GS ,Calvo-Alen J , et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXX: association between C-reactive protein (CRP) gene polymorphisms and vascular events. Rheumatology (Oxford) 2005;44:864-868
CrossRef | Web of Science | Medline31
Kathiresan S ,Melander O ,Guiducci C , et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189-197
CrossRef | Web of Science | Medline32
Willer CJ ,Sanna S ,Jackson AU , et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-169
CrossRef | Web of Science | Medline33
Bansal S ,Buring JE ,Rifai N ,Mora S ,Sacks FM ,Ridker PM . Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309-316
CrossRef | Web of Science | Medline34
Szalai AJ ,Wu J ,Lange EM , et al. Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level. J Mol Med 2005;83:440-447
CrossRef | Web of Science | Medline35
Davey Smith G ,Ebrahim S . `Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1-22
CrossRef | Web of Science | Medline36
Nitsch D ,Molokhia M ,Smeeth L ,DeStavola BL ,Whittaker JC ,Leon DA . Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol 2006;163:397-403
CrossRef | Web of Science | Medline
- Citing Articles (141)
Citing Articles
1
Lyle G. Best, Melanie Nadeau, Kylie Davis, Felicia Lamb, Shellee Bercier, Cindy M. Anderson. (2012) Genetic Variants, Immune Function, and Risk of Pre-Eclampsia among American Indians. American Journal of Reproductive Immunology 67:2, 152-159
CrossRef2
M.C. Calle, M.L. Fernandez. (2012) Inflammation and type 2 diabetes. Diabetes & Metabolism
CrossRef3
Patrik Wennberg, Frances Wensley, Emanuele Di Angelantonio, Lars Johansson, Kurt Boman, Ann Rumley, Gordon Lowe, Göran Hallmans, John Danesh, Jan-Håkan Jansson. (2012) Haemostatic and inflammatory markers are independently associated with myocardial infarction in men and women. Thrombosis Research 129:1, 68-73
CrossRef4
Su Kang Kim, Sung Wook Kang, Dong Hwan Kim, Dong Hwan Yun, Joo-Ho Chung, Ju Yeon Ban. (2011) Matrix Metalloproteinase-3 Gene Polymorphisms Are Associated with Ischemic Stroke. Journal of Interferon & Cytokine Research111216112957005
CrossRef5
Geneviève Faucher, Frédéric Guénard, Luigi Bouchard, Véronique Garneau, Valérie Turcot, Alain Houde, André Tchernof, Jean Bergeron, Yves Deshaies, Frédéric-Simon Hould, Stéfane Lebel, Picard Marceau, Marie-Claude Vohl. (2011) Genetic contribution to C-reactive protein levels in severe obesity. Molecular Genetics and Metabolism
CrossRef6
Mario Di Napoli, Mitchell SV Elkind, Daniel Agustin Godoy, Puneetpal Singh, Francesca Papa, Aurel Popa-Wagner. (2011) Role of C-reactive protein in cerebrovascular disease: a critical review. Expert Review of Cardiovascular Therapy 9:12, 1565-1584
CrossRef7
Young-Sam Kim, Yoon-Kyoung Sung, Chan-Bum Choi, Wan-Sik Uhm, Tae-Hwan Kim, Jin-Ho Shin, Jae-Bum Jun. (2011) The major determinants of arterial stiffness in Korean patients with rheumatoid arthritis are age and systolic blood pressure, not disease-related factors. Rheumatology International
CrossRef8
David D. Ørsted, Børge G. Nordestgaard, Gorm B. Jensen, Peter Schnohr, Stig E. Bojesen. (2011) Prostate-Specific Antigen and Long-Term Prediction of Prostate Cancer Incidence and Mortality in the General Population. European Urology
CrossRef9
Philipp M. Lepper, Marcus E. Kleber, Tanja B. Grammer, Kristina Hoffmann, Simone Dietz, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März. (2011) Lipopolysaccharide-binding protein (LBP) is associated with total and cardiovascular mortality in individuals with or without stable coronary artery disease – Results from the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). Atherosclerosis 219:1, 291-297
CrossRef10
S. Burgess, S. Seaman, D. A. Lawlor, J. P. Casas, S. G. Thompson. (2011) Missing Data Methods in Mendelian Randomization Studies With Multiple Instruments. American Journal of Epidemiology 174:9, 1069-1076
CrossRef11
A. Sicras-Mainar, J. Rejas-Gutiérrez, R. Navarro-Artieda, M. Blanca-Tamayo. (2011) C-reactive protein as a marker of cardiovascular disease in patients with a schizophrenia spectrum disorder treated in routine medical practice. European Psychiatry
CrossRef12
Abhimanyu Garg. (2011) What is the role of alternative biomarkers for coronary heart disease?. Clinical Endocrinology 75:3, 289-293
CrossRef13
M. Thomsen, M. Dahl, A. Tybjaerg-Hansen, B. G. Nordestgaard. (2011) β2-adrenergic receptor Thr164IIe polymorphism, blood pressure and ischaemic heart disease in 66 750 individuals. Journal of Internal Medicineno-no
CrossRef14
Gesina D.S. Ernst, Layla L. de Jonge, Albert Hofman, Jan Lindemans, Henk Russcher, Eric A.P. Steegers, Vincent W.V. Jaddoe. (2011) C-reactive protein levels in early pregnancy, fetal growth patterns, and the risk for neonatal complications: the Generation R Study. American Journal of Obstetrics and Gynecology 205:2, 132.e1-132.e12
CrossRef15
Kristine H. Allin, Børge G. Nordestgaard. (2011) Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Critical Reviews in Clinical Laboratory Sciences 48:4, 155-170
CrossRef16
Ya-Ching Chang, Wei-Ming Wu, Lung-An Hsu. (2011) Lack of association between the genetic variations in the C-reactive protein gene and the risk of psoriasis among the Taiwanese. Molecular Biology Reports
CrossRef17
Naveed Adoni, Ghassan Abusaid, Ken Fujise. 2011. Inflammation and Heart Diseases. .
CrossRef18
Seth S. Martin, Atif N. Qasim, Dan J. Rader, Muredach P. Reilly. (2011) C-Reactive Protein Modifies the Association of Plasma Leptin With Coronary Calcium in Asymptomatic Overweight Individuals. Obesity
CrossRef19
Allegra Battistoni, Speranza Rubattu, Massimo Volpe. (2011) Circulating biomarkers with preventive, diagnostic and prognostic implications in cardiovascular diseases. International Journal of Cardiology
CrossRef20
David E. Kemp, Faramarz Ismail-Beigi, Stephen J. Ganocy, Carla Conroy, Keming Gao, Sarah Obral, Elizabeth Fein, Robert L. Findling, Joseph R. Calabrese. (2011) Use of insulin sensitizers for the treatment of major depressive disorder: A pilot study of pioglitazone for major depression accompanied by abdominal obesity. Journal of Affective Disorders
CrossRef21
Shung-Haur Yang, Chi-Jung Huang, Shih-Ching Chang, Jen-Kou Lin. (2011) Association of C-reactive Protein Gene Polymorphisms and Colorectal Cancer. Annals of Surgical Oncology 18:7, 1907-1915
CrossRef22
Dorothy G. Flood, Gerard J. Marek, Michael Williams. (2011) Developing predictive CSF biomarkers—A challenge critical to success in Alzheimer's disease and neuropsychiatric translational medicine. Biochemical Pharmacology 81:12, 1422-1434
CrossRef23
S. Burgess, S. G. Thompson, . (2011) Avoiding bias from weak instruments in Mendelian randomization studies. International Journal of Epidemiology 40:3, 755-764
CrossRef24
D. Schmidt, A. Kwetkat, M. Gogol. (2011) Chronische Inflammation und Biomarker. Zeitschrift für Gerontologie und Geriatrie 44:3, 153-157
CrossRef25
Zi Li, Arthur CK Chung, Li Zhou, Xiao R Huang, Fei Liu, Ping Fu, J M Fan, Alexander J Szalai, Hui Y Lan. (2011) C-reactive protein promotes acute renal inflammation and fibrosis in unilateral ureteral obstructive nephropathy in mice. Laboratory Investigation 91:6, 837-851
CrossRef26
Stefania Ottaviani, Marina Gorrini, Roberta Scabini, Zamir Kadija, Elena Paracchini, Francesca Mariani, Ilaria Ferrarotti, Maurizio Luisetti. (2011) C reactive protein and alpha1-antitrypsin: relationship between levels and gene variants. Translational Research 157:6, 332-338
CrossRef27
Vera Krane, Christoph Wanner. (2011) Statins, inflammation and kidney disease. Nature Reviews Nephrology 7:7, 385-397
CrossRef28
Cristiano Fava, Martina Montagnana, Gian Cesare Guidi, Olle Melander. (2011) From circulating biomarkers to genomics and imaging in the prediction of cardiovascular events in the general population. Annals of Medicine1-15
CrossRef29
Israel F. Charo, Rebecca Taub. (2011) Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nature Reviews Drug Discovery 10:5, 365-376
CrossRef30
Samir B. Damani, Eric J. Topol. (2011) Emerging Genomic Applications in Coronary Artery Disease. JACC: Cardiovascular Interventions 4:5, 473-482
CrossRef31
T. Sehestedt, S. Lyngbæk, J. Eugen-Olsen, J. Jeppesen, O. Andersen, T.W. Hansen, A. Linneberg, T. Jørgensen, S.B. Haugaard, M.H. Olsen. (2011) Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events. Atherosclerosis 216:1, 237-243
CrossRef32
Benoit J. Arsenault, S. Matthijs Boekholdt, John J. P. Kastelein. (2011) Lipid parameters for measuring risk of cardiovascular disease. Nature Reviews Cardiology 8:4, 197-206
CrossRef33
Børge G Nordestgaard, Anne Tybjærg-Hansen. (2011) Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk. Current Opinion in Lipidology 22:2, 113-122
CrossRef34
Charlotte E. Bolton, Wiebke Schumacher, John R. Cockcroft, Nicholas J. Timpson, George Davey Smith, John Gallacher, Anne Rumley, Gordon D. Lowe, Shah Ebrahim, Dennis J. Shale, Yoav Ben
Shlomo. (2011) The CRP genotype, serum levels and lung function in men: the Caerphilly Prospective Study. Clinical Science 120:8, 347-355
CrossRef35
Thura T. Abd, Danny J. Eapen, Ambareesh Bajpai, Abhinav Goyal, Allen Dollar, Laurence Sperling. (2011) The Role of C-Reactive Protein as a Risk Predictor of Coronary Atherosclerosis: Implications from the JUPITER Trial. Current Atherosclerosis Reports 13:2, 154-161
CrossRef36
Tanja B. Grammer, Michael M. Hoffmann, Wilfried Renner, Marcus E. Kleber, Bernhard R. Winkelmann, Bernhard O. Böhm, Winfried März. (2011) Apolipoprotein E genotypes, circulating C-reactive protein and angiographic coronary artery disease: The Ludwigshafen Risk and Cardiovascular Health Study. Atherosclerosis 215:2, 487-493
CrossRef37
Stig E. Bojesen, Julia S. Johansen, Børge G. Nordestgaard. (2011) Plasma YKL-40 levels in healthy subjects from the general population. Clinica Chimica Acta 412:9-10, 709-712
CrossRef38
Tetsuro Shishido, Tsuneo Konta, Satoshi Nishiyama, Takehiko Miyashita, Takuya Miyamoto, Satoshi Takasaki, Joji Nitobe, Tetsu Watanabe, Yasuchika Takeishi, Isao Kubota. (2011) Suppressive Effects of Valsartan on Microalbuminuria and CRP in Patients with Metabolic Syndrome (Val-Mets). Clinical and Experimental Hypertension 33:2, 117-123
CrossRef39
M. Benn, A. Tybjaerg-Hansen, S. Stender, R. Frikke-Schmidt, B. G. Nordestgaard. (2011) Low-Density Lipoprotein Cholesterol and the Risk of Cancer: A Mendelian Randomization Study. JNCI Journal of the National Cancer Institute 103:6, 508-519
CrossRef40
Christiaan L. Meuwese, Peter Stenvinkel, Friedo W. Dekker, Juan J. Carrero. (2011) Monitoring of inflammation in patients on dialysis: forewarned is forearmed. Nature Reviews Nephrology 7:3, 166-176
CrossRef41
Jesper Johannesen, Jannet Svensson, Regine Bergholdt, Stefanie Eising, Hanne Gramstrup, Erik Frandsen, Jens Dick-Nielsen, Lars Hansen, Flemming Pociot, Henrik B Mortensen, . (2011) Hypoglycemia, S-ACE and ACE genotypes in a Danish nationwide population of children and adolescents with type 1 diabetes. Pediatric Diabetes 12:2, 100-106
CrossRef42
Idan Roifman, Paul L. Beck, Todd J. Anderson, Mark J. Eisenberg, Jacques Genest. (2011) Chronic Inflammatory Diseases and Cardiovascular Risk: A Systematic Review. Canadian Journal of Cardiology 27:2, 174-182
CrossRef43
Jeppe Zacho, Shiva Yazdanyar, Stig E. Bojesen, Anne Tybjaerg-Hansen, Børge G. Nordestgaard. (2011) Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: Cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls. International Journal of Cancer 128:3, 644-652
CrossRef44
Stefan Stender, Ruth Frikke-Schmidt, Børge G. Nordestgaard, Anne Tybjaerg-Hansen. (2011) Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population. Hepatology 53:2, 640-648
CrossRef45
N J Timpson, B G Nordestgaard, R M Harbord, J Zacho, T M Frayling, A Tybjærg-Hansen, G Davey Smith. (2011) C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. International Journal of Obesity 35:2, 300-308
CrossRef46
Viviane Zorzanelli Rocha, Eduardo J. Folco. (2011) Inflammatory Concepts of Obesity. International Journal of Inflammation 2011, 1-14
CrossRef47
Livija Deban, Sebastien Jaillon, Cecilia Garlanda, Barbara Bottazzi, Alberto Mantovani. (2011) Pentraxins in innate immunity: lessons from PTX3. Cell and Tissue Research 343:1, 237-249
CrossRef48
Hannah S. Mumby, Cathy E. Elks, Shengxu Li, Stephen J. Sharp, Kay-Tee Khaw, Robert N. Luben, Nicholas J. Wareham, Ruth J. F. Loos, Ken K. Ong. (2011) Mendelian Randomisation Study of Childhood BMI and Early Menarche. Journal of Obesity 2011, 1-6
CrossRef49
Oh Young Bang. (2011) Biomarkers of Stroke. Korean Journal of Stroke 13:2, 57
CrossRef50
J. KLOVAITE, M. BENN, S. YAZDANYAR, B. G. NORDESTGAARD. (2011) High platelet volume and increased risk of myocardial infarction: 39 531 participants from the general population. Journal of Thrombosis and Haemostasis 9:1, 49-56
CrossRef51
Adriana M Hung, T Alp Ikizler, Marie R Griffin, Kimberly Glenn, Robert A Greevy, Carlos G Grijalva, Edward D Siew, Dana C Crawford. (2011) CRP polymorphisms and chronic kidney disease in the third national health and nutrition examination survey. BMC Medical Genetics 12:1, 65
CrossRef52
Kristine H Allin, Børge G Nordestgaard, Henrik Flyger, Stig E Bojesen. (2011) Elevated pre-treatment levels of plasma C-reactive protein are associated with poor prognosis after breast cancer: a cohort study. Breast Cancer Research 13:3, R55
CrossRef53
S. MATSUDA, A. YAMASHITA, Y. SATO, S. KITAJIMA, T. KOIKE, C. SUGITA, S. MORIGUCHI-GOTO, K. HATAKEYAMA, M. TAKAHASHI, C. KOSHIMOTO, Y. MATSUURA, T. IWAKIRI, Y. E. CHEN, J. FAN, Y. ASADA. (2011) Human C-reactive protein enhances thrombus formation after neointimal balloon injury in transgenic rabbits. Journal of Thrombosis and Haemostasis 9:1, 201-208
CrossRef54
Atif N. Qasim, Venkata Budharaju, Nehal N. Mehta, Caitlin St Clair, Samira Farouk, Seth Braunstein, Mark Schutta, Nayyar Iqbal, Daniel J. Rader, Muredach P. Reilly. (2011) Gender differences in the association of C-reactive protein with coronary artery calcium in Type-2 diabetes. Clinical Endocrinology 74:1, 44-50
CrossRef55
Gregory A Sgueglia, Filippo Crea. (2010) The risks of a new hypothesis: why did JUPITER patients have almost twice the predicted event rate of reduction?. Journal of Cardiovascular Medicine1
CrossRef56
Ming-Yow Hung, Kuang-Hung Hsu, Ming-Jui Hung, Chi-Wen Cheng, Wen-Jin Cherng. (2010) Interactions among gender, age, hypertension and C-reactive protein in coronary vasospasm. European Journal of Clinical Investigation 40:12, 1094-1103
CrossRef57
Ian J. Brown, Paul Elliott. (2010) Recent Findings from Mendelian Randomization Studies of Cardiovascular Disease. Current Cardiovascular Risk Reports 4:6, 429-436
CrossRef58
Giampaolo Niccoli, Rocco A. Montone, Giuseppe Ferrante, Filippo Crea. (2010) The Evolving Role of Inflammatory Biomarkers in Risk Assessment After Stent Implantation. Journal of the American College of Cardiology 56:22, 1783-1793
CrossRef59
Florian Kronenberg, Claudia Lamina. (2010) The evaporation of positive genetic association findings. When time has come to go. Atherosclerosis 213:1, 30-32
CrossRef60
Raffaele De Caterina, Marika Massaro, Egeria Scoditti, Maria Annunziata Carluccio. (2010) Pharmacological modulation of vascular inflammation in atherothrombosis. Annals of the New York Academy of Sciences 1207:1, 23-31
CrossRef61
R. J. Bisoendial, S. M. Boekholdt, M. Vergeer, E. S. G. Stroes, J. J. P. Kastelein. (2010) C-reactive protein is a mediator of cardiovascular disease. European Heart Journal 31:17, 2087-2091
CrossRef62
T. Mölkänen, A. Rostila, E. Ruotsalainen, M. Alanne, M. Perola, A. Järvinen. (2010) Genetic polymorphism of the C-reactive protein (CRP) gene and a deep infection focus determine maximal serum CRP level in Staphylococcus aureus bacteremia. European Journal of Clinical Microbiology & Infectious Diseases 29:9, 1131-1137
CrossRef63
Robert S. Rosenson, Colin Hislop, Michael Elliott, Yuri Stasiv, Michael Goulder, David Waters. (2010) Effects of Varespladib Methyl on Biomarkers and Major Cardiovascular Events in Acute Coronary Syndrome Patients. Journal of the American College of Cardiology 56:14, 1079-1088
CrossRef64
Kiran Musunuru, Sekar Kathiresan. (2010) Genetics of Coronary Artery Disease. Annual Review of Genomics and Human Genetics 11:1, 91-108
CrossRef65
Juan J. Carrero, Peter Stenvinkel. (2010) Inflammation in End-Stage Renal Disease-What Have We Learned in 10 Years?. Seminars in Dialysis 23:5, 498-509
CrossRef66
Chris J Packard. (2010) Optimizing lipid-lowering therapy in the prevention of coronary heart disease. Expert Review of Clinical Pharmacology 3:5, 649-661
CrossRef67
A Ramel, J A Martinez, M Kiely, N M Bandarra, I Thorsdottir. (2010) Effects of weight loss and seafood consumption on inflammation parameters in young, overweight and obese European men and women during 8 weeks of energy restriction. European Journal of Clinical Nutrition 64:9, 987-993
CrossRef68
Chung-Feng Huang, Ming-Yen Hsieh, Jeng-Fu Yang, Wu-Cheng Chen, Ming-Lun Yeh, Ching-I Huang, Chia-Yen Dai, Ming-Lung Yu, Zu-Yau Lin, Shinn-Chern Chen, Wan-Long Chuang, Jee-Fu Huang. (2010) Serum hs-CRP was correlated with treatment response to pegylated interferon and ribavirin combination therapy in chronic hepatitis C patients. Hepatology International 4:3, 621-627
CrossRef69
Yu Wang, Zong-Mei Bian, Wen-Zhen Yu, Zheng Yan, Wei-Chih Chen, Xiao-Xin Li. (2010) Induction of interleukin-8 gene expression and protein secretion by C-reactive protein in ARPE-19 cells. Experimental Eye Research 91:2, 135-142
CrossRef70
Ali A. Rizvi. (2010) Hypertension, Obesity, and Inflammation: The Complex Designs of a Deadly Trio. Metabolic Syndrome and Related Disorders 8:4, 287-294
CrossRef71
Alexandre B. Rosendo, Luciana O. Lima, Felipe Dal-Pizzol, Silvana Almeida. (2010) Lipid and C-Reactive Protein Levels, Cardiovascular Disease Risk Factors and Simvastatin Treatment in Brazilian Individuals. Inflammation 33:4, 244-250
CrossRef72
Xiangjun Yang, Wenzhi Hu, Qin Zhang, Yueying Wang, Lie Sun. (2010) Puerarin Inhibits C-Reactive Protein Expression via Suppression of Nuclear Factor κB Activation in Lipopolysaccharide-Induced Peripheral Blood Mononuclear Cells of Patients with Stable Angina Pectoris. Basic & Clinical Pharmacology & Toxicology 107:2, 637-642
CrossRef73
S. Yazdanyar, B. G. Nordestgaard. (2010) NOD2/CARD15 genotype, cardiovascular disease and cancer in 43 600 individuals from the general population. Journal of Internal Medicine 268:2, 162-170
CrossRef74
Sarah C.W. Marott, Børge G. Nordestgaard, Jeppe Zacho, Jens Friberg, Gorm B. Jensen, Anne Tybjærg-Hansen, Marianne Benn. (2010) Does Elevated C-Reactive Protein Increase Atrial Fibrillation Risk?. Journal of the American College of Cardiology 56:10, 789-795
CrossRef75
J. J. FREIBERG, A. TYBJAERG-HANSEN, B. G. NORDESTGAARD. (2010) Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50 000 individuals. Journal of Thrombosis and Haemostasis 8:8, 1694-1701
CrossRef76
, T. K. Hansen, C. Forsblom, M. Saraheimo, L. Thorn, J. Wadén, P. Høyem, J. Østergaard, A. Flyvbjerg, P.-H. Groop. (2010) Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes. Diabetologia 53:7, 1517-1524
CrossRef77
J. Zacho, A. Tybjaerg-Hansen, B. G. Nordestgaard. (2010) C-reactive protein and all-cause mortality--the Copenhagen City Heart Study. European Heart Journal 31:13, 1624-1632
CrossRef78
Petter Quist-Paulsen. (2010) Statins and inflammation: an update. Current Opinion in Cardiology 25:4, 399-405
CrossRef79
D. Deepak, C. Daousi, M. Javadpour, D. Clark, Y. Perry, J. Pinkney, I.A. MacFarlane. (2010) The influence of growth hormone replacement on peripheral inflammatory and cardiovascular risk markers in adults with severe growth hormone deficiency. Growth Hormone & IGF Research 20:3, 220-225
CrossRef80
J. Gustav Smith, Christopher Newton-Cheh. (2010) Genetic Loci Associated with C-Reactive Protein Levels and Risk Of Coronary Heart Disease. Current Cardiovascular Risk Reports 4:3, 178-180
CrossRef81
M. Verduijn, B. Siegerink, K. J. Jager, C. Zoccali, F. W. Dekker. (2010) Mendelian randomization: use of genetics to enable causal inference in observational studies. Nephrology Dialysis Transplantation 25:5, 1394-1398
CrossRef82
Hyeon Chang Kim, Philip Greenland, Jacques E. Rossouw, JoAnn E. Manson, Barbara B. Cochrane, Norman L. Lasser, Marian C. Limacher, Donald M. Lloyd-Jones, Karen L. Margolis, Jennifer G. Robinson. (2010) Multimarker Prediction of Coronary Heart Disease Risk. Journal of the American College of Cardiology 55:19, 2080-2091
CrossRef83
Irving Kushner, David Samols, Marina Magrey. (2010) A unifying biologic explanation for “high-sensitivity” C-reactive protein and “low-grade” inflammation. Arthritis Care & Research 62:4, 442-446
CrossRef84
Anne Hedegaard, Rasmus Sejersten Ripa, Julia S. Johansen, Erik Jørgensen, Jens Kastrup. (2010) Plasma YKL-40 and recovery of left ventricular function after acute myocardial infarction. Scandinavian Journal of Clinical & Laboratory Investigation 70:2, 80-86
CrossRef85
Ingrid Meulenbelt, Steffan D. Bos, Margreet Kloppenburg, Nico Lakenberg, Jeanine J. Houwing-Duistermaat, Iain Watt, Anton J. de Craen, Cornelia M. van Duijn, P. Eline Slagboom. (2010) Interleukin-1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study. Arthritis & Rheumatism 62:4, 1119-1126
CrossRef86
A. T. Yan, R. T. Yan, M. Cushman, A. Redheuil, R. P. Tracy, D. K. Arnett, B. D. Rosen, R. L. McClelland, D. A. Bluemke, J. A.C. Lima. (2010) Relationship of interleukin-6 with regional and global left-ventricular function in asymptomatic individuals without clinical cardiovascular disease: insights from the Multi-Ethnic Study of Atherosclerosis. European Heart Journal 31:7, 875-882
CrossRef87
Diljit Kaur-Knudsen, Børge Grønne Nordestgaard, Stig Egil Bojesen. (2010) CYP2C9 genotype does not affect risk of tobacco-related cancer in the general population. Cancer Epidemiology 34:2, 178-183
CrossRef88
Ambareesh Bajpai, Abhinav Goyal, Laurence Sperling. (2010) Should We Measure C-reactive Protein on Earth or Just on JUPITER?. Clinical Cardiology 33:4, 190-198
CrossRef89
P. Libby, F. Crea. (2010) Clinical implications of inflammation for cardiovascular primary prevention. European Heart Journal 31:7, 777-783
CrossRef90
Stefan Löffler, Mignon Löffler-Ensgraber, Karin Fehsel, Ansgar Klimke. (2010) Clozapine therapy raises serum concentrations of high sensitive C-reactive protein in schizophrenic patients. International Clinical Psychopharmacology 25:2, 101-106
CrossRef91
Jacques Genest. (2010) C-reactive protein: Risk factor, biomarker and/or therapeutic target?. Canadian Journal of Cardiology 26, 41A-44A
CrossRef92
J. David Spence. (2010) The role of lipoprotein(a) in the formation of arterial plaques, stenoses and occlusions. Canadian Journal of Cardiology 26, 37A-40A
CrossRef93
Barbara Bottazzi, Andrea Doni, Cecilia Garlanda, Alberto Mantovani. (2010) An Integrated View of Humoral Innate Immunity: Pentraxins as a Paradigm. Annual Review of Immunology 28:1, 157-183
CrossRef94
Peter P Toth, Peter A McCullough, Michael S Wegner, Kenneth J Colley. (2010) Lipoprotein-associated phospholipase A 2 : role in atherosclerosis and utility as a cardiovascular biomarker. Expert Review of Cardiovascular Therapy 8:3, 425-438
CrossRef95
Jaroslav A. Hubacek, Anne Peasey, Hynek Pikhart, Petr Stavek, Ruzena Kubinova, Michael Marmot, Martin Bobak. (2010) APOE polymorphism and its effect on plasma C-reactive protein levels in a large general population sample. Human Immunology 71:3, 304-308
CrossRef96
K. H. Allin, B. G. Nordestgaard, J. Zacho, A. Tybjaerg-Hansen, S. E. Bojesen. (2010) C-Reactive Protein and the Risk of Cancer: A Mendelian Randomization Study. JNCI Journal of the National Cancer Institute 102:3, 202-206
CrossRef97
S. Yazdanyar, B. G. Nordestgaard. (2010) NOD2/CARD15 genotype and common gastrointestinal diseases in 43 600 individuals. Journal of Internal Medicine 267:2, 228-236
CrossRef98
Paul M. Maciocia. (2010) Inflammatory Signaling in Pulmonary Arterial Hypertension: The Controversial Role of CRP, and the Search for New Therapies. Cardiovascular Therapeutics 28:1, 1-4
CrossRef99
Alfredo Bardají, José A. Barrabés, Juan Sanchis, Pedro L. Sánchez. (2010) Actualización en cardiopatía isquémica. Revista Española de Cardiología 63, 49-60
CrossRef100
Hong Yao, Peiying Shi, Ling Zhang, Xiaohui Fan, Qing Shao, Yiyu Cheng. (2010) Untargeted metabolic profiling reveals potential biomarkers in myocardial infarction and its application. Molecular BioSystems 6:6, 1061
CrossRef101
Amish A Patel, Matthew J Budoff. (2010) Screening for heart disease: C-reactive protein versus coronary artery calcium. Expert Review of Cardiovascular Therapy 8:1, 125-131
CrossRef102
(2010) C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. The Lancet 375:9709, 132-140
CrossRef103
Terumasa Inoue, Makoto Kawai, Tokiko Nakane, Ayumi Nojiri, Kosuke Minai, Kimiaki Komukai, Takayuki Ogawa, Kenichi Hongo, Masato Matsushima, Michihiro Yoshimura. (2010) Influence of Low-Grade Inflammation on Plasma B-type Natriuretic Peptide Levels. Internal Medicine 49:24, 2659-2668
CrossRef104
Vicente Bertomeu Martínez, J. Ramón González-Juanatey. (2009) Markers of Inflammation and Cardiovascular Disease. American Journal Cardiovascular Drugs 9:Supplement 1, 3-7
CrossRef105
Mahir Karakas, Wolfgang Koenig. (2009) CRP in Cardiovascular Disease. Herz 34:8, 607-613
CrossRef106
Christine A. Curcio, Mark Johnson, Jiahn-Dar Huang, Martin Rudolf. (2009) Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins. Progress in Retinal and Eye Research 28:6, 393-422
CrossRef107
K. Park, M. Steffes, D.-H. Lee, J. H. Himes, D. R. Jacobs. (2009) Association of inflammation with worsening HOMA-insulin resistance. Diabetologia 52:11, 2337-2344
CrossRef108
Marshall A. Corson. (2009) Emerging inflammatory markers for assessing coronary heart disease risk. Current Cardiology Reports 11:6, 452-459
CrossRef109
B.G. Nordestgaard, J. Zacho. (2009) Lipids, atherosclerosis and CVD risk: Is CRP an innocent bystander?. Nutrition, Metabolism and Cardiovascular Diseases 19:8, 521-524
CrossRef110
Børge G Nordestgaard. (2009) Does elevated C-reactive protein cause human atherothrombosis? Novel insights from genetics, intervention trials, and elsewhere. Current Opinion in Lipidology 20:5, 393-401
CrossRef111
D Kaur-Knudsen, S E Bojesen, B G Nordestgaard. (2009) Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals. The Pharmacogenomics Journal 9:5, 327-332
CrossRef112
Pia R Kamstrup, Børge G Nordestgaard. (2009) Lipoprotein(a) should be taken much more seriously. Biomarkers in Medicine 3:5, 439-441
CrossRef113
Gelin Xu, Zhiming Zhou, Wusheng Zhu, Xiaobing Fan, Xinfeng Liu. (2009) Plasma C-reactive protein is related to cognitive deterioration and dementia in patients with mild cognitive impairment. Journal of the Neurological Sciences 284:1-2, 77-80
CrossRef114
Ya-Hong Ma, Lei Zhao, Xun-De Xian, Dorothy Yang, Wei Huang, Yu-Hui Wang, Odilo Mueller, Elaine Chang, Yves Konigshofer, Mark Van-Cleve, George Liu, Jin-Kui Yang. (2009) A case-control study on the relationship between HDL2b and non-alcoholic fatty liver disease in Chinese type 2 diabetic patients. Clinical Chemistry and Laboratory Medicine 47:9, 1067-1072
CrossRef115
Einor Ben Assayag, Shani Shenhar-Tsarfaty, Irena Bova, Shlomo Berliner, Sali Usher, Hava Peretz, Itzhak Shapira, Natan M. Bornstein. (2009) Association of the -757T>C polymorphism in the CRP gene with circulating C-reactive protein levels and carotid atherosclerosis. Thrombosis Research 124:4, 458-462
CrossRef116
Diljit Kaur-Knudsen, Børge G. Nordestgaard, Anne Tybjaerg-Hansen, Stig E. Bojesen. (2009) CYP1B1 genotype and risk of cardiovascular disease, pulmonary disease, and cancer in 50 000 individuals. Pharmacogenetics and Genomics 19:9, 685-694
CrossRef117
Francisco AH Fonseca, Maria Cristina O Izar. (2009) Primary prevention of vascular events in patients with high levels of C-reactive protein: the JUPITER study. Expert Review of Cardiovascular Therapy 7:9, 1041-1056
CrossRef118
Oliver Zimmermann, Magdalena Bienek-Ziolkowski, Bettina Wolf, Martin Vetter, Regine Baur, Volker Mailänder, Vinzenz Hombach, Jan Torzewski. (2009) Myocardial inflammation and non-ischaemic heart failure: is there a role for C-reactive protein?. Basic Research in Cardiology 104:5, 591-599
CrossRef119
Maria Adriana Sardo, Giuseppe Mandraffino, Salvatore Campo, Carlo Saitta, Alessandra Bitto, Angela Alibrandi, Stefania Riggio, Egidio Imbalzano, Antonino Saitta. (2009) Biglycan expression in hypertensive subjects with normal or increased carotid intima-media wall thickness. Clinica Chimica Acta 406:1-2, 89-93
CrossRef120
Dorette Raaz, Martin Herrmann, Arif B. Ekici, Lutz Klinghammer, Berthold Lausen, Reinhard E. Voll, Jeanette H.W. Leusen, Jan G.J. van de Winkel, Werner G. Daniel, André Reis, Christoph D. Garlichs. (2009) FcγRIIa genotype is associated with acute coronary syndromes as first manifestation of coronary artery disease. Atherosclerosis 205:2, 512-516
CrossRef121
Amit V. Khera, Daniel J. Rader. (2009) Discovery and Validation of New Molecular Targets in Treating Dyslipidemia: The Role of Human Genetics. Trends in Cardiovascular Medicine 19:6, 195-201
CrossRef122
D. C. Wheeler. (2009) The Jupiter trial--new territory for statins?. Nephrology Dialysis Transplantation 24:7, 2036-2037
CrossRef123
Jaime García de Tena. (2009) Rosuvastatin, C-reactive protein, LDL cholesterol, and the JUPITER trial. The Lancet 374:9683, 24
CrossRef124
Christoph Wanner, Christiane Drechsler, Vera Krane. (2009) C-Reactive Protein and Uremia. Seminars in Dialysis 22:4, 438-441
CrossRef125
Jeremiah P Depta, Richard A Krasuski. (2009) Therapy and clinical trials. Current Opinion in Lipidology 20:3, 262-263
CrossRef126
Fadi G. Hage, Rajesh Venkataraman, Gilbert J. Zoghbi, Gilbert J. Perry, Angelo M. DeMattos, Ami E. Iskandrian. (2009) The Scope of Coronary Heart Disease in Patients With Chronic Kidney Disease. Journal of the American College of Cardiology 53:23, 2129-2140
CrossRef127
Himadri Roy, Shalini Bhardwaj, Seppo Yla-Herttuala. (2009) Molecular genetics of atherosclerosis. Human Genetics 125:5-6, 467-491
CrossRef128
Ralph AH Stewart. (2009) Predicting benefit from statins by C-reactive protein, LDL-cholesterol or absolute cardiovascular risk. Future Cardiology 5:3, 231-236
CrossRef129
Shi Du Yan, Angelika Bierhaus, Peter P Nawroth, David M Stern. (2009) Endothelial Precursor Cells and CRP on the RAGE: Activation or Cell Death?. Journal of Cardiovascular Pharmacology 53:5, 349-351
CrossRef130
Sonny Dandona, Robert Roberts. (2009) Creating a genetic risk score for coronary artery disease. Current Atherosclerosis Reports 11:3, 175-181
CrossRef131
Javier Sanz, Pedro R. Moreno, Valentin Fuster. (2009) The Year in Atherothrombosis. Journal of the American College of Cardiology 53:15, 1326-1337
CrossRef132
Jacob J. Freiberg, Morten Dahl, Anne Tybjærg-Hansen, Peer Grande, Børge G. Nordestgaard. (2009) Leukotriene C4 synthase and ischemic cardiovascular disease and obstructive pulmonary disease in 13,000 individuals. Journal of Molecular and Cellular Cardiology 46:4, 579-586
CrossRef133
Andrew S. Plump, Pek Yee Lum. (2009) Genomics and Cardiovascular Drug Development. Journal of the American College of Cardiology 53:13, 1089-1100
CrossRef134
(2009) C-reactive protein: a predictive marker, not a causal factor, for cardiovascular disease. Nature Clinical Practice Cardiovascular Medicine 6:3, 160-160
CrossRef135
Pascal J. Goldschmidt-Clermont. (2009) Jay and Jeanie Schottenstein Prize in Cardiovascular Science: Predicting Cardiovascular Illnesses for the 21 st Century, and the Unpredictable …. Antioxidants & Redox Signaling 11:3, 401-406
CrossRef136
(2009) Genetically Elevated C-Reactive Protein and Vascular Disease. New England Journal of Medicine 360:9, 933-935
Full Text137
K. Graf. (2009) Die JUPITER-Studie: Primärprävention bei erhöhtem C-reaktivem Protein. Der Kardiologe 3:1, 35-36
CrossRef138
(2009) High levels of C-reactive protein do not increase the risk of ischemic vascular disease. Nature Clinical Practice Endocrinology & Metabolism 5:2, 64-64
CrossRef139
Konstantinos Tziomalos, Vasilios G. Athyros, Asterios Karagiannis, Dimitri P. Mikhailidis. (2009) JUPITER: major implications for vascular risk assessment. Current Medical Research and Opinion 25:1, 133-137
CrossRef140
Schunkert, Heribert, Samani, Nilesh J., . (2008) Elevated C-Reactive Protein in Atherosclerosis — Chicken or Egg?. New England Journal of Medicine 359:18, 1953-1955
Full Text141
R. S Vasan. (2008) Commentary: C-reactive protein and risk prediction--moving beyond associations to assessing predictive utility and clinical usefulness. International Journal of Epidemiology 38:1, 231-234
CrossRef
- Letters
