Abstract
Type 2 diabetes has a replicated linkage on chromosome12q24.2 (NIDDM2 locus/non-insulin-dependent diabetes mellitus 2 locus), near the HNF-1α/MODY3 gene. The MODY3 gene is not responsible for this linkage. PSMD9 - contributing to T2D in Italians by rare unique mutations and by the common haplotype A/T/G - lies in the NIDDM2 region. By genotyping the two markers D12S1721/D12S2073 nearby the MODY3 gene in our unrelated T2D cases, we previously excluded that the PSMD9 SNPs are in linkage disequilibrium (LD) with the MODY3 gene. In the present study, we aimed at identifying whether the PSMD9 A/T/G haplotype is present in the Italy-1 and Italy-3 MODY3 families and whether it cosegregates with diabetes/MODY3. We raised the question whether there is a digenic additive model within the MODY3 families to which the PSMD9 A/T/G haplotype contributes. We demonstrated that the PSMD9 A/T/G haplotype is linked to the MODY3 established mutations in the Italy-1 and Italy-3 families. By non-parametric and parametric linkage analyses, and LD modeling, in the Italy-1 and Italy-3 families we hereby show that the MODY3 mutation and the PSMD9 IVS3+nt460A/IVS3+nt437T/ G197 SNPs act in an additional model to cause diabetes. Since in the two MODY3 Italian families the PSMD9 A/T/G haplotype is linked to MODY3, it contributes to MODY3/diabetes via an additional model. All MODY3 families should be tested for the PSMD9 A/T/G haplotype. The potential clinical impact of our study is of relevance.