Inflammation

Inflammation is a key component of atherosclerosis, and genes coding for inflammatory proteins and cytokines are therefore good candidates for coronary heart disease risk. Inflammation is characterized by a local reaction, which may be followed by activation of systemic acute phase reactant proteins [such as C-reactive protein (CRP) and interleukin6 (IL6)], which are associated with increased cardiovascular risk.

C-Reactive Protein (CRP)

CRP has emerged as a strong, independent predictor of vascular risk and is associated with endothelial dysfunction (112-116). Recent studies have also demonstrated a relationship between increased pulse pressure, PWV, and CRP (117,118). Recently, we demonstrated a link between CRP and pulse pressure and PWV in apparently healthy individuals (119). Some common polymorphisms (—717G>A and +1441C>T) have been identified in the chromosome 1-located CRP gene. In the Brull et al. (120) study, the +1444T allele was associated significantly with the elevated CRP levels, even after adjustments for other confounding factors. In healthy subjects, the +1444TT homozygotes had higher CRP levels than +1444C allele carriers, both at baseline and after exercise. In coronary artery bypass graft (CABG) patients, genotype did not influence the baseline CRP, although +1444TT homozygotes had raised CRP levels compared with the +1444C allele carriers. This result is in keeping with the hypothesis that this variant increases susceptibility to vascular disease. However, if the CRP level is a marker for, rather than a mediator of, atherosclerosis, then future studies of this polymorphisms will be required to establish the genotype-specific risk thresholds for CRP in the prediction of CHD risk.

Interleukin6 (IL6)

IL6 is a pleiotropic cytokine involved in the regulation of the acute phase response. Elevated levels of IL6 are associated with the development and severity of coronary disease (121,122). Two common polymorphisms (—174 G>C and -572 G>C) have been identified in the promoter region of the IL6 gene located on chromosome 22. The role of IL6 in determining the pathogenesis of aneurysmal disease is evidenced by the finding that — 174 C allele carriers have increased IL6 levels and display increased mortality with a relative risk of 2.95 over a 5-year follow-up period (123). In patients with CABG, 6 hours after the procedure, peak IL6 levels rose to a significantly higher level in patients with the — 572C allele (CC and CG genotypes) than in those with the — 572GG genotype (124). In the same cohort, the — 174CC homozygotes had significantly elevated IL6 levels, when compared with — 174G allele carriers. These effects were significant even after adjustment for other variables. Two other studies also demonstrated the link between the — 174C allele and higher CHD mortality (125,126). In the WOSCOPS study, subjects with the — 174CC genotype and on medication exhibited a reduced risk of coronary heart diseases with pravas-tatin treatment (127). These results strongly support the role of the genotype not just with plasma IL6 levels in an acute inflammatory situation but also with mortality.

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