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

Abstract

Carotid artery stenosis (CS) is a well-established risk factor for stroke. Increased proinflammatory chemokines, enhanced metallothionein (MT), and altered metal homeostasis may play roles in atherosclerosis progression and plaque destabilization. MT may sequester zinc during chronic inflammation, provoke zinc deficiency, and modulate NK cell cytotoxicity. A recent investigation of older patients with diabetes and atherosclerosis showed an association between the -209 A/G MT2A polymorphism, CS, and zinc status. In this study, we evaluated the relationship between two MT2A polymorphisms (-209 and + 838 locus), metal status, and inflammatory/immune response in older patients with CS only (the CS1 group) or with CS and previous cerebrovascular episodes (transient ischemic attack or stroke) (the CS2 group). A total of 506 individuals (188 CS1, 100 CS2, and 218 healthy controls) were studied. Atherosclerotic patients (CS1 and CS2) showed increased levels of MT, MCP-1, and RANTES, reduced NK cell cytotoxicity, and altered trace element concentrations (zinc, copper, magnesium, iron). The +838 C/G MT2A polymorphism was differently distributed in CS1 and CS2 patients, who displayed the GG genotype (C-) with significantly higher frequency than elderly controls. C-carriers showed increased MCP-1 and decreased NK cell cytotoxicity, CD56+ cells, and intracellular zinc availability along with decreased zinc, copper, and magnesium content in erythrocytes and increased iron in plasma. C-carriers also showed a major incidence of soft carotid plaques. In conclusion, the +838 C/G MT2A polymorphism seems to influence inflammatory markers, zinc availability, NK cell cytotoxicity, and trace element status, all of which may promote CS development.

Genetic Variation at a Metallothionein2APromoter Single-Nucleotide Polymorphism in White and Black Females in Midwestern United States

“…Metallothionein 2A polymorphisms have recently been studied for their associations with risk for a variety of diseases, such as type II diabetes mellitus, atherosclerosis, and carotid artery stenosis (Giacconi et al, 2005(Giacconi et al, , 2007a(Giacconi et al, , 2007b(Giacconi et al, , 2008Yang et al, 2008). In addition to these chronic diseases, metallothionein 2A polymorphisms may account for some of the variability in Cd concentration (Bjorkman et al, 2000) and thereby influence breast and endometrial cancer risk development (McElroy et al, 2006;Akesson et al, 2008).…”

Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population

“…Plasma Zn and Cu were determined by a Thermo XII Series ICP-MS (Thermo Electron Corporation, Waltham, MA, USA) following the manufacturer's application note (AN_EO604) which was slightly modified in the manner previously described (Giacconi et al 2007). …”

Association of MT1A haplotype with cardiovascular disease and antioxidant enzyme defense in elderly Greek population: comparison with an Italian cohort

“…Several investigators report hypozincemia in atherosclerosis and CVD [8,9] or a zinc dyshomeostasis during myocardial ischemia-reperfusion model [10]. In addition, longitudinal or nested case-control studies, within a prospective population, describe the general involvement of zinc deficiency in increased CVD mortality [11], especially in the presence of concomitant dysmetabolism of other trace elements [12].…”