Causal Role Of C-reactive Protein Research Articles

The causal role of C-reactive protein and interleukin-6 on anxiety and depression symptoms and life satisfaction: Mendelian randomisation analyses in the HUNT study.

Serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) have been associated with anxiety and depression in cross-sectional and Mendelian randomisation studies, but results regarding the effect size and direction have been mixed. A recent Mendelian Randomisation (MR) study suggested that CRP may decrease and IL-6 may increase anxiety and depression symptoms. Among 68 769 participants of the population-based Trøndelag Health Study (HUNT), we performed cross-sectional observational and one-sample MR analyses of serum CRP and two-sample MR analysis of serum IL-6. The main outcomes were symptoms of anxiety and depression assessed using the Hospital Anxiety and Depression Scale (HADS) and life satisfaction assessed using a seven-level ordinal questionnaire where higher scores indicate lower life satisfaction. In cross-sectional observational analyses, a doubling in serum CRP level was associated with 0.27% (95% CI -0.20 to 0.75) difference in HADS depression score (HADS-D), -0.77% (95% CI -1.24 to -0.29) difference in HADS anxiety score (HADS-A) and -0.10% (95% CI -0.41 to 0.21) difference in life satisfaction score. In one-sample MR analyses, a doubling in serum CRP was associated with 2.43% (95% CI -0.11 to 5.03) higher HADS-D, 1.94% (95% CI -0.58 to 4.52) higher HADS-A, and 2.00% (95% CI 0.45 to 3.59) higher life satisfaction score. For IL-6, causal point estimates were in the opposite direction, but imprecise and far from conventional criteria for statistical significance. Our results do not support a major causal role of serum CRP on anxiety and depression symptoms and life satisfaction, but provides weak evidence that serum CRP may modestly increase anxiety and depression symptoms and reduce life satisfaction. Our findings do not support the recent suggestion that serum CRP may lower anxiety and depression symptoms.

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5× 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

Apolipoprotein E genotypes, circulating C-reactive protein and angiographic coronary artery disease: The Ludwigshafen Risk and Cardiovascular Health Study

C-reactive protein (CRP) has been implicated in the development of atherosclerosis. The genetic polymorphism of apolipoprotein (apo) E is associated with the concentration of CRP. We analyzed the association between the apo E genotype, CRP and angiographic coronary artery disease (CAD). The concentration of CRP was similar in patients with stable CAD and in controls, but increased in patients presenting with acute coronary syndromes. In models adjusting for the main confounding variables, the alleles ɛ4 and ɛ2 were associated with decreased and increased concentrations of CRP, respectively, compared to the wild-type allele ɛ3. In spite of this, the ɛ2 allele was associated with a lower prevalence of angiographic CAD, while the slight over-representation of the ɛ4 allele was statistically not significant. We conclude that the apo E genotype is associated with circulating CRP. A causal role of CRP in the development of CAD would be supported if genotypes that raise CRP in the long-term were themselves associated with CAD. As we found the opposite, we suggest that the association between CRP and cardiovascular events reflects confounding and reverse causation.

Estimating the causal role of C-reactive protein in coronary heart disease: Collaborative mendelian randomization analysis

Background and methods: It has been suggested that long-term average (i.e., “usual”) concentration of C-reactive protein (CRP), a sensitive circulating down-stream marker of inflammation, may be causally relevant to coronary heart disease (CHD). We used individual-records from 180K participants in 46 studies (including 42K CHD patients) to assess associations of 4 SNPs that reflect all common variation in the CRP gene in European populations (rs3093077, rs1205, rs1130864, rs1800947) with: CRP concentration, other risk factors, and CHD risk. We compared risk ratios (RRs) for CHD with genetically elevated CRP to equivalent differences in CRP concentration itself.

Plasma RANTES: a molecular fingerprint of the unstable carotid plaque?

This editorial refers to ‘Relationship between circulating levels of RANTES (regulated on activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study’, by S.S. Virani et al . doi:10.1093/eurheartj/ehq367 Rupture of atherosclerotic plaques in epicardial coronary or carotid arteries may lead to myocardial infarction or stroke—the leading causes of morbidity and mortality in Western countries.1 Thus, timely detection of these unstable plaques before they rupture is a great medical need.2 Non-invasive plaque visualization using duplex ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) provide the advantage of longitudinal analyses, but limitations exist in terms of moderate spatial resolution and exposure to X-rays when using CT. Hence, their sensitivity and specificity for detecting unstable atherosclerotic plaques is moderate. To optimize the cost–benefit ratio, we need to tailor our tools for identifying patients with increased cardiovascular risk harbouring plaques prone to rupture. Ideally, high-resolution plaque imaging is combined with one or several emerging biomarkers that provide incremental information about plaque biology and patient prognosis. Adding to the wealth of experimental, clinical, and epidemiological evidence that identified inflammation as an integral element throughout the different stages of atherosclerosis, biomarkers of inflammation have been validated in clinical trials.1,3 Among them, C-reactive protein stands out as the prototype inflammatory biomarker that adds valuable information in terms of cardiovascular risk stratification.1 However, in the absence of firm evidence for a causal role of C-reactive protein in atherosclerosis by applying Mendelian randomization for gene variants in the C-reactive protein locus,4 C-reactive protein does not meet the criteria of a cardiovascular risk factor. Several additional inflammatory mediators involved in experimental atherogenesis have been tested clinically with regard to their prognostic … *Corresponding author. Tel: +41 44 635 64 67, Fax: +41 44 635 68 27, Email: christian.matter{at}access.uzh.ch

Paradoxical association of C-reactive protein with endothelial function in rheumatoid arthritis.

BackgroundWithin the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA).Methodology/Principal FindingsPatients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01).Conclusions/SignificanceThese findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability.

C-reactive protein genotypes associated with circulating C-reactive protein but not with angiographic coronary artery disease: the LURIC study

Circulating C-reactive protein is associated with future cardiovascular events. The causal role of C-reactive protein in the development of atherosclerosis remains controversial. We analysed the association between three genetic polymorphisms (PM) (-717C>T, rs2794521; +1059G>C, rs1800947; +1444C>T, rs1130864) at the C-reactive protein locus and related haplotypes with both circulating C-reactive protein and angiographic coronary artery disease (CAD). The concentration of C-reactive protein was similar in patients with stable CAD and in controls, but increased in patients presenting with acute coronary syndromes. In models adjusting for the main confounding variables, the minor alleles of the +1059G>C (rs1800947) and the +1444C>T PM (rs1130864) were associated with decreased and increased concentrations of C-reactive protein, respectively. Haplotypes 1 and 4 decreased, and haplotype 2 increased C-reactive protein, whereas haplotype 3 had no appreciable effect. None of the genetic variants affecting circulating C-reactive protein was consistently associated with the prevalence of angiographic CAD. A causal role of C-reactive protein in the development of CAD would require that genetic PM resulting in long-term modulation of the concentration of C-reactive protein be themselves associated with CAD. We were not able to detect such a relationship, which can be attributed to either a very small genetic effect size or the relationship between C-reactive protein and cardiovascular events may reflect confounding and reverse causation.

C-reactive protein: a cardiovascular risk factor report on the CRP hot-topic workshop October 1, 1997

On October 1, 1997, a 1 day hot-topic workshop on C-reactive protein (CRP) was organized in Leiden, the Netherlands, aiming at further evaluating the importance of inflammation as a critical mechanism in cardiovascular disease. C-reactive protein (CRP) is an acute phase protein that is associated with risk of cardiovascular events in healthy individuals and patients with angina pectoris. At the workshop, several investigators who are the pioneers in studies on CRP as a cardiovascular risk factor presented the latest data and their views on the topic. The discussions were designed to evaluate where we stand at present, and what should be done in the near future to promote evidence-based diagnostics and evidence-based intervention/ prevention strategies. The discussion focussed on the association between CRP and cardiovascular disease (CVD), a possible causal role of CRP in CVD, the effect of drugs on CRP levels, the role of infectious agents in the relation between CRP and CVD, and the measurement of low levels of CRP. Although many questions remained, the meeting resulted in a better insight into the role of CRP in cardiovascular disease and a basis for further studies in this area. © Harcourt Brace and Co. Ltd 1998.