title: +647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications.
abstract: Diabetes mellitus is a chronic disease characterized by an overproduction of reactive oxygen species, which perturbs zinc metabolism and promotes the onset of cardiovascular disease (CVD) in diabetic patients. Metallothioneins (MT) are cysteine-rich metal-binding proteins which, by means of their antioxidant and zinc-buffering properties, might prevent the development of diabetic cardiovascular complications. A recent investigation shows that a polymorphism (+647 A/C) in the human MT-1A gene, affects the intracellular zinc ion release (iZnR) from the proteins and is associated with longevity in Italian population. The aim of the present study is to assess the involvement of +647 A/C and +1245 A/G MT1A polymorphisms with the susceptibility to type 2 diabetes (DM2) and cardiovascular complications. The study included 694 old individuals: 242 old healthy controls, 217 DM2 patients without clinical evidence of CVD (DNC) and 235 diabetic patients with diagnosis of CVD (DCVD). +647 A/C MT1A polymorphism, but not the second SNP, was associated with DM2. C allele carriers were more prevalent in DNC and DCVD patients than in control group (OR=1.37, p=0.034; OR=1.54, p=0.002, respectively). C+ carriers was associated with higher glycemia and glycosylated hemoglobin in DCVD patients, but not in DNC or control subjects. No differences in plasma zinc, but a modulation of MT levels and iZnR in PBMCs were observed in DCVD cohort when related to +647 A/C MT1A polymorphism. In summary, this work provides novel evidence on the association of the +647 A/C MT1A polymorphism with DM2. Moreover, C+ carriers in DCVD patients presented a worse glycemic control, a reduced iZnR and a higher MT levels, suggesting a possible role of MT in diabetic cardiovascular complications.
authors.affiliation: Immunology Center (Section Nutrition, Immunity and Ageing), Research Department INRCA, via Birarelli 8, 60121 Ancona, Italy. rogiacconi@libero.it
authors.forename: R
authors.initials: R
authors.lastname: Giacconi
authors.forename: A R
authors.initials: AR
authors.lastname: Bonfigli
authors.forename: R
authors.initials: R
authors.lastname: Testa
authors.forename: C
authors.initials: C
authors.lastname: Sirolla
authors.forename: C
authors.initials: C
authors.lastname: Cipriano
authors.forename: M
authors.initials: M
authors.lastname: Marra
authors.forename: E
authors.initials: E
authors.lastname: Muti
authors.forename: M
authors.initials: M
authors.lastname: Malavolta
authors.forename: L
authors.initials: L
authors.lastname: Costarelli
authors.forename: F
authors.initials: F
authors.lastname: Piacenza
authors.forename: S
authors.initials: S
authors.lastname: Tesei
authors.forename: E
authors.initials: E
authors.lastname: Mocchegiani
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics*; D048909:Diabetes Complications / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008668:Metallothionein / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015032:Zinc / Q000097:blood / Q000378:metabolism
chemical_list: C530099:MT1A protein, human; D008668:Metallothionein; D015032:Zinc