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• W2022272358 abstract "C-reactive protein and cardiovascular risk Over the past decade, the inflammatory process and factors that contribute to variations in chronic low-grade inflammation have been linked to the prognosis of cardiovascular disease. C-reactive protein (CRP) is now a well-recognized systemic inflammatory marker, characterizing a pro-inflammatory state when it is increased. Although CRP is considered to be an acute phase protein, low plasma levels have been shown to be remarkably stable over time. A high-sensitivity assay for CRP (hs-CRP) is now available. Hs-CRP levels higher than 3 mg/l appear to be of value in predicting cardiovascular events [1–3], whereas levels above 10 mg/l reflect an acute inflammatory condition rather than chronic low-grade inflammation. In particular, CRP is found to predict cardiovascular risk in patients with acute coronary syndromes and chronic coronary disease [4]. Recent studies also suggest that high hs-CRP levels may predict the risk of coronary artery restenosis after angioplasty [5]. Hypertension is characterized by increased vascular resistance due, in large part, to endothelial dysfunction and vascular remodelling, with recent animal and human investigations showing that pro-inflammatory components are also involved in these processes. There is general agreement on a positive association between low-grade inflammation and arterial stiffness, but it is not yet clear whether, how and why chronic hypertension promotes inflammatory processes. Several studies have suggested an independent role of CRP in the risk for future hypertension development [6]. C-reactive protein and metabolic syndrome Metabolic syndrome may well not be a specific disease, but rather a clustering of metabolic and cardiovascular risk factors. Using the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), ATP III guideline definition and recent data from the National Health and Nutrition Examination Survey, the estimated prevalence of metabolic syndrome was suggested to be 27% in the adult US population [7]. ATP III has identified six major components of metabolic syndrome: abdominal obesity, atherogenic dyslipidemia, increased blood pressure, insulin resistance, a prothrombotic state and a proinflammatory state. The proinflammatory state is currently evaluated by hs-CRP assay. In patients with metabolic syndrome, cardiovascular risk rises in proportion to increases in hs-CRP concentrations. Previous studies have demonstrated that CRP is elevated with several measurable components of metabolic syndrome, including hypertension, dyslipidemia, obesity and glucose intolerance [8–13], and it is also associated with more difficult measurable factors, such as fibrinolysis and endothelial dysfunction. Hs-CRP, increasing with the total number of risk factors of metabolic syndrome, was recently shown to add prognostic information beyond that provided by metabolic syndrome. Thus, in patients with established coronary artery disease, the presence of metabolic syndrome and elevated hs-CRP may identify a particularly high-risk group that may benefit from more aggressive therapy [14]. From a marker of risk to a key factor of the cardiovascular disease inflammatory process? In several studies involving a large number of subjects, CRP appeared to be at least as strong as and even a stronger predictor of cardiovascular events than low-density lipoprotein (LDL) cholesterol, adding prognostic information at all levels of calculated Framingham risk and of metabolic syndrome. CRP levels of < 1, 1–3 and > 3 mg/l correspond to low, moderate and high-risk groups for future cardiovascular events [3]. However, there is still much debate about the usefulness of knowing hs-CRP levels in a particular individual. The American Heart Association and the Centers for Disease Control and Prevention published a joint scientific statement about using inflammatory markers in clinical and public health practice. This statement was developed after systematically reviewing the evidence of an association mainly between CRP and coronary heart disease and stroke (www.americanheart.org). It has emphasized that the true independent predictive value of hs-CRP and new cardiovascular events is still uncertain. Thus, monitoring is not required if an individual's cardiovascular risk score is low (judged by global risk assessment) or high (greater than 20% in 10 years). High-risk patients should be treated intensively, regardless of their hs-CRP levels. Monitoring hs-CRP can help predict a cardiovascular and stroke event, and help direct further evaluation and therapy in patients with a risk score in the intermediate range (10–20% in 10 years). Interestingly, CRP could be an early marker of hypertension. CRP levels are higher in patients with high normal blood pressure compared to a normotensive population. The predictive value of CRP and blood pressure is additive on cardiovascular risk. Furthermore, CRP appears to be an independent risk factor for hypertension development in previously normotensive individuals [15], and its evaluation may thus shed new light on the relevance of so-called ‘pre-hypertension’ or ‘high normal blood pressure’ as currently being debated. Besides being a marker of inflammation and a risk marker of cardiovascular events, CRP could play a pivotal role in atherogenesis. CRP increases the release of inflammatory cytokines, enhances the binding of monocytes to the endothelium, and favours macrophage foam cell formation [16–18]. CRP was also recently shown to decrease endothelial nitric oxide production while increasing the expression of endothelin-1, endothelial cell adhesion molecules, plasminogen activator [19–23] and LOX-1, endothelial receptor-1 of oxidized LDL [24]. All these components contribute to endothelial dysfunction, a common feature of hypertension, atherosclerosis and metabolic syndrome. Heritability estimates of C-reactive protein Much of the inter-individual variability in CRP remains unexplained. For example, in the Family Heart Study, only 20–30% of variability in CRP was explained by environmental factors [25]. This suggests that low-grade inflammation is, to some degree, inherited. Several studies have estimated the heritability of CRP to be between 0.3 and 0.4 in sibling pairs of Caucasian, Japanese and Native American families, after adjusting for sex and age [25–28]. A more direct estimate can be calculated in monozygotic twins. Retterstol et al. [29] studied healthy monozygotic twins and, as reported in this issue of the journal, Wessel et al. [30] estimated heritability with the classical twin method, using both monozygotic and dizygotic twin pair correlations. In both studies, an important genetic contribution to the control of CRP levels was found; the within-pair correlation coefficient was 0.4 in the study by Retterstol et al. [29], and 0.56 ± 0.7 in the study by Wessel et al. [30]. It is speculated that excessive adipose tissue in subjects with metabolic syndrome could lead to overproduction of pro-inflammatory cytokines, including CRP. Although adjusting for body mass index (BMI), which is strongly associated with CRP levels and is a highly heritable phenotype (also in relation to hypertension) [31], could theoretically reduce the estimated heritability, a recent Diabetes Heart Study showed that the degree of heritability of CRP was not significantly decreased after adjustment for BMI [32]. It concluded that the heritability of CRP levels could not be explained solely by that of BMI. Convincingly, Wessel et al. [30] documented the shared genetic determination of CRP and BMI. The twin design allowed Wessel et al. [30] to identify shared genetic determinants between CRP and several features of metabolic syndrome. These included BMI, blood pressure, leptin and lipids. In subjects with established hypertension, hs-CRP levels were associated not only with higher blood pressure, but also with BMI, insulin and HOMA (index of insulin resistance), leptin, triglycerides and norepinephrine. The study by Wessel et al. [30] demonstrates that inter-individual variations in CRP levels are substantially determined by independent as well as shared genetic factors, and lays the ground work for identifying genes contributing to these variations. Genetic contribution to C-reactive protein levels Evidence of a significant association between CRP gene and CRP levels was found in some [33,34] but not all [32] studies pointing to the contribution of other genetic factors. Thus, an association between CRP levels and apolipoprotein E [32], tumour necrosis factor-α and interleukin-6 promoter polymorphisms was noted. Wessel et al. [30] identified a novel pathophysiological link that involves catecholamine biosynthesis, β-adrenergic stimulation and CRP production. In their study, CRP levels were significantly associated with genetic polymorphisms in a rate-limiting enzyme of catecholamine biosynthesis, tyrosine hydroxylase (for which the authors previously found that common allelic determinants within the tyrosine hydroxylase locus explained inter-individual variations in catecholamine production) and two β-adrenergic receptors: ADRB1 and ADRB2. The non-synonymous single nucleotide polymorphism (SNP) in ADRB1 was shown to lead to lower cAMP production in response to agonist stimulation in vitro, whereas the SNP haplotype in the ADRB2 promoter analysed was found to affect transcription of the gene. This emphasizes the biological relevance of the study by Wessel et al. [30]. Epinephrine is known to simulate CRP biosynthesis and release from hepatocytes, and patient treatments with β-adrenergic antagonists have been demonstrated to lower circulating CRP levels. The functional nature of the polymorphisms investigated by Wessel et al. [30] adds to the importance of their study. However, it is noteworthy that urinary catecholamine concentrations were associated with CRP levels only in the group of subjects with hypertension. The authors explained this apparent discrepancy by the fact that urinary epinephrine levels are only a pale reflection of critical intra-synaptic concentrations. Nevertheless, this new pathogenetic link revealed by genetic study opens a new area of interaction between the adrenergic system and inflammation. Although the candidate gene approach in SNP association studies used by Wessel et al. [30] has led to the identification of a new pathophysiological link between CRP and the adrenergic system, a more assumption-free type of approach (e.g. employing whole genome SNP association studies, which is now possible with the newly-available high-density SNP-chips; 500 000 SNP) will help to identify all possible associations and possibly unexpected novel pathogenetic links, as well as their relative importance in the determination of CRP levels and other inflammatory markers, perhaps providing clues in the general link between inflammation and metabolic syndrome. The complexity and pleiotropism of these types of studies will have to call upon Systems Biology tools [35]." @default.
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• W2022272358 title "Genetic determinants of C-reactive protein levels in metabolic syndrome: a role for the adrenergic system?" @default.
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