Our study shows that the
PSMD9 SNPs studied are in linkage with hypercholesterolemia in the Italian T2D families, thus making
PSMD9 a possible risk gene for hypercholesterolemia. However, these findings should be replicated in families with hypercholesterolemia of other ethnicities and in particular in all ethnical groups in which the chromosome 12q24 locus was reported as linked to elevated cholesterol [
1,
2] to confirm the general relevance of the gene in other populations as well.
The finding of our study may have an inestimable impact given the relevance of the 12q24 locus in hypercholesterolemia in several ethnical groups [
1,
2] as well as the importance of hypercholesterolemia as a major risk factor for macrovascular disease and cerebral and cardiovascular events reducing quality of life and lifetime span [
3]. Given the
PSMD9 linkage reported with T2D-nephropathy [
8] and with macrovascular pathology [
9] as well, it is possible that the PSMD9 has pleiotropic effects contributing to the phenotypes associated with macrovascular pathology as well as with T2D. PSMD9 is present at high concentrations in eukaryotic cells and is part of the 26S proteasome complex, which contributes to the degradation of intracellular proteins in antigenic peptides in the immune response to antigen presentation by MHC class I cells (
http://www.genecards.org/cgi-bin/carddisp.pl?gene=PSMD9). Thus, one potential role of PSMD9 in the phenotypes associated with T2D and atherosclerosis could be related to a direct role in the pathogenesis of inflammation as an autoimmune process [
12]. In addition, PSMD9 is mediating the magnitude and duration of the transcription of the ligand-dependent retinoid-target genes (
http://www.millipore.com/pathways/pathviewer.do?pathwayId=76). Thus, PSMD9 may, if impaired in its function due to gene variants affecting the protein sequence and/or protein dosage, alter dosage and effects of several downstream genes. In transgenic mice with pancreatic overexpression of the homologous of PSMD9, it has been shown that the increased dose of the PSMD9 protein is causing insulin deficiency and diabetes as well as hypertriglyceridemia [
10]. In addition, an inhibition of the gene transcription in vitro also reduces insulin secretion [
13]. Thus, the hypothesis is that given the complex network of transcription and co-activator factors that PSMD9 is associated to, both PSMD9 reduced or increased protein dose in the cell may have pathogenetic effects, by potentially contributing to phenotypes that may be either different or having an underlying contributing factor.