Involvement of −308 TNF-α and 1267 Hsp70-2 polymorphisms and zinc status in the susceptibility of coronary artery disease (CAD) in old patients

Abstract

Coronary artery disease (CAD) is characterized by an inflammatory status and it represents the major cause of death in elderly. Zinc deficiency and inflammatory genes within major histocompatibility complex (MHC) region are implicated in ischaemic heart diseases. TNF-alpha is present in coronary artery plaques and may provoke plaque instability. Hsp70 plays instead a pro-atherogenic role, via proinflammatory cytokine production, in atherosclerotic lesions contributing to plaque rupture. Contradictory data report the association between -308 TNF-alpha polymorphism and CAD, while no investigations exist on Hsp70-2 gene in CAD. In the current study, we analysed -308 TNF-alpha and 1267 Hsp70-2 polymorphisms and zinc status in 190 healthy old controls and 216 old patients with carotid stenosis subdivided in two groups: the first one 105 patients with CAD (C group), and the second one 111 patients without cardiovascular events (D group). We found a lack of association between -308 TNF-alpha polymorphism and CAD. Conversely, 1267 Hsp70-2 polymorphism was associated with CAD. In particular, significant higher frequency of AB + BB genotypes (B + genotype) was observed in C patients than controls (71.4 vs.56.9%, P = 0.017, odds ratio = 1.898). However, when C patients were subdivided into four subgroups on the basis of presence/absence of 1267B Hsp70-2 and -308A TNF-alpha alleles, B + A + patients showed higher prothrombin activity as well as Hsp70-2, TNF-alpha, IL-6 gene expressions in carotid atheroma when compared to B - A - genotypes. The zinc status (plasma and Zn/Fe ratio in erythrocytes) is not affected by these polymorphisms. However, zinc deficiency is present in CAD condition. In conclusion, 1267 HSP70-2 polymorphism and zinc deficiency, rather than -308 TNF-alpha, are independently associated with CAD. B + A+ and B + A- carriers seem more predisposed to ischaemic events; conversely, B - A- genotype may be considered a protective marker against CAD.

The +838 C/G MT2A Polymorphism, Metals, and the Inflammatory/Immune Response in Carotid Artery Stenosis in Elderly People

“…This finding is in agreement with the decreased plasma zinc concentration observed in patients suffering from coronary artery disease (33). In CS patients, zinc deficiency may be responsible for decreased NK cell activity and enhanced plasma concentrations of MCP-1 and RANTES.…”

“…High MT levels during aging are correlated with low zinc availability and impaired inflammatory immune response, likely contributing to the development of age-related diseases, including atherosclerosis (16,15,26,32). Indeed, zinc deficiency has been suggested as a risk factor for atherosclerosis development (6,33), because the cation acts as a cofactor of antioxidant enzymes and protects from lipid peroxidation (34).…”

Interaction of serum 70-kDa heat shock protein levels and HspA1B (+1267) gene polymorphism with disease severity in patients with chronic heart failure

“…An adenine (A) to guanine (G) polymorphism at HspA1B +1267 has been described; however, the polymorphism does not lead to any amino acid change in the Hsp70 protein. Carriage of the G allele is associated with increased risks and poor outcomes in different diseases (Balog et al 2005;Giacconi et al 2005;Klausz et al 2005;Giacconi et al 2006). Results about the effect of the polymorphism on the HspA1B messenger RNA (mRNA) levels are controversial (Pociot et al 1993;Schroeder et al 2000;Giacconi et al 2005), whilst according to our best knowledge, the direct association with the serum Hsp70 level has never been reported.…”

Zinc–gene interaction related to inflammatory/immune response in ageing

“…However, further investigations are required in order to clarify why centenarians and centenarian offspring have lower levels of serum HSP70 and to better understand the role played by zinc and genetic polymorphisms in this observation. At our knowledge, there is an isolated study investigating the role of 1267 HSP70-2 polymorphisms and zinc status on the risk of coronary artery disease [58]. This study reported an association of 1267 HSP70-2 polymorphism with coronary artery disease, but the zinc status (plasma and Zn/Fe ratio in erythrocytes) was not affected by the polymorphism.…”