PSMD9 gene in the NIDDM2 locus is linked to type 2 diabetes in Italians

Abstract

Type 2 diabetes (T2D) has a replicated linkage on chromosome12q24.2, the non-insulin-dependent-diabetes 2 (NIDDM2) locus. PSMD9 (which rarely causes T2D in Italians) lies in the NIDDM2 region and is implicated in beta cell insulin transcription and diabetes onset in mice. Thus, PSMD9 is a candidate T2D gene for the NIDDM2 locus. Weaimed at identifying any linkage of the PSMD9 A/T/G haplotype, or of any of its single variants, to Italian T2D siblings/families. We screened 201 T2D siblings/families for PSMD9 variants and performed a parametric and non-parametric linkage study, including linkage disequilibrium (LD) modeling and simulation analyses. Our results show a consistent significant LODscore in linkage with T2D for each single PSMD9 SNP variant (IVS3+nt460A, P=3.546E-007, IVS3+nt437T, P=7.723E-008, and 197G, P=4.921E-007) and for the haplotype (A/T/G for the above-cited variants, P=3.078E-015) using the non-parametric analysis, as well as the LD modeling test ( P=4.178E-009) and the parametric linkage analysis. The strongest signal is present under the recessive model ( P=4.905E-011). Our statistical power in the present study relies on the presence of T2D affected siblings, which represent an ideal dataset to identify linkage with a recessive disease model. Our 1,000 simulation analyses, performed for each single test, confirm that the results are not due to random chance. In summary, the A/T/G haplotype in PSMD9 is linked via the recessive allelic model to T2D in Italians. By our observation and testing, the linkage strategy can identify a gene contributing to T2D in a homogeneous subject dataset. © 2009 Wiley-Liss, Inc.