Abstract
BackgroundThe 12q24 locus entails at least one gene responsible for hypercholesterolemia. Within the 12q24 locus lies the gene of proteasome modulator 9 (PSMD9). PSMD9 is in linkage with type 2 diabetes (T2D), T2D-nephropathy and macrovascular pathology in Italian families and PSMD9 rare mutations contribute to T2D.AimsIn the present study, we aimed at determining whether the PSMD9 T2D risk single nucleotide polymorphisms (SNPs) IVS3 + nt460 A > G, IVS3 + nt437 T > C and E197G A > G are linked to hypercholesterolemia in 200 T2D Italian families.MethodsWe characterized 200 Italian families for presence and/or absence of hypercholesterolemia characterized by LDL levels ≥ 100 mg/dl in drug-naïve patients and/or presence of a diagnosis of hypercholesterolemia in a patient treated with statin medication. The phenotypes were described as unknown in all cases in which the diagnosis was either unclear or the data were missing. We tested in the 200 Italians families for evidence of linkage of the PSMD9 SNPs with hypercholesterolemia. The non-parametric linkage analysis was performed for the qualitative phenotype by using the Merlin software; the Lod score and correspondent P-value were calculated. For the significant linkage score, 1000 replicates were performed to calculate the empirical P-value.ResultsThe PSMD9 gene SNPs studied show linkage to hypercholesterolemia. The results are not due to random chance.ConclusionsPSMD9 should be tested in all populations reporting linkage to hypercholesterolemia within the chromosome 12q24 locus. The impact of this gene on hypercholesterolemia and contribution to cardio- and cerebrovascular events may be high.
Highlights
The chromosome 12q24 locus is linked to dyslipidemia and hypercholesterolemia and must entail at least one gene responsible for these phenotypes [1,2]
We reported that proteasome modulator 9 (PSMD9) rarely causes type 2 diabetes (T2D) by unique mutations [5] and that the PSMD9 IVS3 + nt460 A > G, IVS3 + nt437 C > T and E197G A > G single nucleotide polymorphisms (SNPs) are linked to late-onset T2D via the recessive model [6] and to MODY3 [7] via the additive model
Our study shows that the PSMD9 SNPs studied are in linkage with hypercholesterolemia in the Italian T2D families, making PSMD9 a possible risk gene for hypercholesterolemia
Summary
The chromosome 12q24 locus is linked to dyslipidemia and hypercholesterolemia and must entail at least one gene responsible for these phenotypes [1,2]. Dyslipidemia is an important cardiovascular risk factor for T2D. Within the 12q24 locus is located the gene of proteasome modulator 9 (PSMD9). We aimed at identifying in the present study whether the coactivator of insulin transcription PSMD9 may contribute to linkage to hypercholesterolemia in 200 Italian T2D families. The 12q24 locus entails at least one gene responsible for hypercholesterolemia. Within the 12q24 locus lies the gene of proteasome modulator 9 (PSMD9). PSMD9 is in linkage with type 2 diabetes (T2D), T2D-nephropathy and macrovascular pathology in Italian families and PSMD9 rare mutations contribute to T2D
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