The-8 UTR C/G polymorphism of PSMA6 gene is associated with susceptibility to myocardial infarction in type 2 diabetic patients

Aims: Controversial results have been provided regarding the potential role of proteasome subunit alpha type 6 gene (PSMA6) in determining susceptibility to myocardial infarction (MI). In addition, no data in Caucasians have been provided. We aimed to: (a) validate in a Caucasian population the association between PSMA6 gene polymorphism and MI; (b) investigate the potential association between PSMA6 gene variants and MI in type 2 diabetics; (c) evaluate a potential functional role of PSMA6,allelic variants. Methods: 224 subjects (73 patients with MI and 151 controls) were genotypized for variants of PSMA6 gene. In 36 patients, biopsy specimens were taken from the left ventricle area of presumed ischemia for ubiquitin-proteasome activity quantification. Results: Allele frequency and genotype distribution of all PSMA6 gene polymorphisms Studied did not differ between patients with MI and controls. When the analysis was restricted to type 2 diabetics (n = 119), a different rs_1048990 C/G allele frequency and genotype distribution was found having diabetic subjects with MI (n = 34) higher G allele frequency compared to controls (n = 85), (P = 0.02). Myocardial ubiquitin levels (r = 0.75; p < 0.001) and proteasome 20S (r = 0.7; p < 0.01) activity significantly correlated with plasma glucose even after adjusting for covariates. Type 2 diabetic subjects had higher myocardial ubiquitin levels (p, < 0.001) and proteasome 20S activity (p < 0.001) compared to non-diabetics. Subjects carriers the allele G at rs_1048990 loci had higher myocardial ubiquitin levels and proteasome 20S activity. Conclusion: PSMA6rs_1048990 polymorphism may contribute to MI susceptibility in type 2 diabetes. Up-regulation of ubiquitin-proteasome pathway may be a potential mechanism for explaining such association. (C) 2008 Elsevier Ireland Ltd. All rights reserved.