Proteasome modulator 9 and macrovascular pathology of T2D

Coronary artery disease (CAD) and stroke share a major linkage at the chromosome 12q24 locus. The same chromosome region entails at least a major risk gene for type 2 diabetes (T2D) within NIDDM2, the non-insulin-dependent-diabetes 2 locus. The gene of proteasome modulator 9 (PSMD9) lies in the NIDDM2 region and is implicated in diabetes in mice. PSMD9 mutations rarely cause T2D and common variants are linked to both late-onset T2D and maturity-onset-diabetes of the young (MODY3). In this study, we aimed at determining whether PSMD9 is linked to macrovascular pathology of T2D.

In our 200 T2D families from Italy, we characterized the clinical phenotype of macrovascular pathology by defining the subjects for presence or absence of CAD, stroke and/or transitory ischemic attacks (TIA), plaques of the large arterial vessels (macro-vasculopathy) and arterial angioplasty performance. We then screened 200 T2D siblings/families for PSMD9 +nt460A/G, +nt437C/T and exon E197G A/G single nucleotide polymorphisms (SNPs) and performed a non-parametric linkage study to test for linkage for coronary artery disease, stroke/TIA, macro-vasculopathy and macrovascular pathology of T2D. We performed 1,000 replicates to test the power of our significant results. Our results show a consistent significant LOD score in linkage with all the above-mentioned phenotypes. Our 1000 simulation analyses, performed for each single test, confirm that the results are not due to random chance.

In summary, the PSMD9 IVS3+nt460A/G, +nt437C/T and exon E197G A/G SNPs are linked to CAD, stroke/TIA and macrovascular pathology of T2D in Italians.