Abstract
The locus 12q24 is linked to type 2 diabetes (T2D) and to changes in retinal vascular caliber in Caucasians. Proteasome Modulator 9 gene (PSMD9) lies in the 12q24 locus and is implicated in diabetes onset and in degradation of intracellular proteins in antigenic peptides in the immune response to antigen presentation by MHC class I cells. Within PSMD9, we reported a linkage to T2D and to MODY3 in Italian families. We recently demonstrated a linkage of the PSMD9 T2D risk SNPs with T2D-nephropathy, T2D-neuropathy, retinopathy, hypercholesterolemia, and macrovascular pathology. We aimed at studying the presence of the linkage signal of the PSMD9 T2D risk SNPs IVS3+nt460, IVS3+nt437, E197G to microvascular pathology associated to T2D in Italian siblings/families. We screened 200 T2D siblings/families for the PSMD9 above-mentioned variants and performed a parametric and non-parametric linkage study by Merlin software. Our results show significant LOD score in linkage with microvascular pathology for the PSMD9 SNPs studied using the non-parametric and parametric linkage analysis. The strongest signal is present under the recessive model. Our statistical power relies on the presence of T2D affected siblings, which represent an ideal dataset to identify linkage with a recessive disease model. Our simulation analysis confirms that the results are not due to random chance. In summary, the PSMD9 IVS3+nt460, IVS3+nt437, E197G SNPs are linked via the recessive model to microvascular pathology of T2D in Italians. A possible role of PSMD9 in microvascular pathology may be related to a causative pathogenetic role in inflammation as part of an autoimmune process.