Proteasome Modulator 9 SNPs are linked to hypertension in type 2 diabetes families

<p>Abstract</p> <p>Background</p> <p>Chromosome 12q24 was recently associated with hypertension. Proteasome Modulator 9 (<it>PSMD9</it>) lies in the 12q24 locus and is in linkage with MODY3, type 2 diabetes (T2D), microvascular and macrovascular pathology, carpal tunnel syndrome, and hypercholesterolemia in Italian families.</p> <p>Aims</p> <p>Our goal was to determine whether <it>PSMD9 </it>is linked to elevated blood pressure/hypertension in T2D families.</p> <p>Methods</p> <p>We characterized the Italian T2D families' members for presence and/or absence of elevated blood pressure (≥ 130/80) and/or hypertension. The phenotypes were described as unknown in all cases in which the diagnosis was either unclear or the data were not available for the subject studied. We tested in the 200 Italians families for the presence of the linkage of the <it>PSMD9 </it>T2D risk single nucleotide polymorphisms (SNPs) <it>IVS3+nt460 A > G</it>, <it>IVS3+nt437 T > C </it>and <it>E197G A > G </it>with elevated blood pressure/hypertension. The non-parametric linkage analysis was performed for this qualitative phenotype by using the Merlin software; the Lod score and correspondent P-value were calculated. Parametric linkage analysis was also performed. For the significant linkage score, 1000 replicates were run to calculate the empirical P-value.</p> <p>Results</p> <p>The <it>PSMD9 </it>gene SNPs studied are in linkage with elevated blood pressure/hypertension in our Italian families.</p> <p>Conclusions</p> <p>We conclude that the <it>PSMD9 </it>gene and/or any variant in linkage disequilibrium with the SNPs studied contribute to the linkage to hypertension within our family dataset. This is the first report of <it>PSMD9 </it>linkage to hypertension within the 12q24 locus.</p

Hypercholesterolemia and a candidate gene within the 12q24 locus

<p>Abstract</p> <p>Background</p> <p>The 12q24 locus entails at least one gene responsible for hypercholesterolemia. Within the 12q24 locus lies the gene of proteasome modulator 9 (<it>PSMD9</it>). <it>PSMD9 </it>is in linkage with type 2 diabetes (T2D), T2D-nephropathy and macrovascular pathology in Italian families and <it>PSMD9 </it>rare mutations contribute to T2D.</p> <p>Aims</p> <p>In the present study, we aimed at determining whether the <it>PSMD9 </it>T2D risk single nucleotide polymorphisms (SNPs) <it>IVS3 + nt460 A > G, IVS3 + nt437 T > C </it>and <it>E197G A > G </it>are linked to hypercholesterolemia in 200 T2D Italian families.</p> <p>Methods</p> <p>We 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 <it>PSMD9 </it>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.</p> <p>Results</p> <p>The <it>PSMD9 </it>gene SNPs studied show linkage to hypercholesterolemia. The results are not due to random chance.</p> <p>Conclusions</p> <p><it>PSMD9 </it>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.</p

Proteasome modulator 9 and macrovascular pathology of T2D

<p>Abstract</p> <p>Aims</p> <p>Coronary artery disease (CAD) and stroke share a major linkage at the chromosome 12q24 locus. The same chromosome region entails at least a major risk gene for type 2 diabetes (T2D) within NIDDM2, the non-insulin-dependent-diabetes 2 locus. The gene of Proteasome Modulator 9 (<it>PSMD9) </it>lies in the NIDDM2 region and is implicated in diabetes in mice. <it>PSMD9 </it>mutations rarely cause T2D and common variants are linked to both late-onset T2D and maturity-onset-diabetes of the young (MODY3). In this study, we aimed at determining whether <it>PSMD9 </it>is linked to macrovascular pathology of T2D.</p> <p>Methods and Results</p> <p>In our 200 T2D families from Italy, we characterized the clinical phenotype of macrovascular pathology by defining the subjects for presence or absence of CAD, stroke and/or transitory ischemic attacks (TIA), plaques of the large arterial vessels (macro-vasculopathy) and arterial angioplasty performance. We then screened 200 T2D siblings/families for <it>PSMD9 +nt460A/G</it>, <it>+nt437C/T </it>and exon <it>E197G A/G </it>single nucleotide polymorphisms <it>(</it>SNPs) and performed a non-parametric linkage study to test for linkage for coronary artery disease, stroke/TIA, macro-vasculopathy and macrovascular pathology of T2D. We performed 1,000 replicates to test the power of our significant results. Our results show a consistent significant LOD score in linkage with all the above-mentioned phenotypes. Our 1000 simulation analyses, performed for each single test, confirm that the results are not due to random chance.</p> <p>Conclusions</p> <p>In summary, the <it>PSMD9 IVS3+nt460A/G</it>, <it>+nt437C/T </it>and exon <it>E197G A/G SNPs </it>are linked to CAD, stroke/TIA and macrovascular pathology of T2D in Italians.</p

CDK4 IVS4-nt40 AA genotype and obesity-associated tumors/cancer in Italians – a case-control study

<p>Abstract</p> <p>Background</p> <p>Cell cycle checkpoint regulation is crucial for prevention of tumor in mammalian cells. Cyclin-dependant kinase 4 (CDK4) is important in cell cycle regulation, as it controls the G1-S phase of the cell cycle. CDK4 has potential mitogenic properties through phosphorylation of target proteins. We aimed at identifying a role of <it>CDK4 </it>IVS4-nt40 G→A gene variant in benign and/or malignant tumors and in obesity-associated benign and/or malignant tumors in an Italian adult subject dataset.</p> <p>Methods</p> <p>We recruited 263 unrelated Italian subjects: 106 subjects had at least one benign tumor and 46 subjects had at least one malignant tumor, while 116 subjects had at least two tumors and/or cancers. We collected BMI data for 90% of them: 186 subjects had a BMI≥30 Kg/m²and 52 subjects had a BMI ≥ 30 Kg/m². We performed statistical power calculations in our datasets. DNA samples were directly sequenced with specific primers for the <it>CDK4 </it>IVS4-nt40 G→A variant. Genotype association tests with disease were performed.</p> <p>Results</p> <p>In our study, no significant association of the <it>CDK4 </it>IVS4-nt40 AA genotype with cancer and/or tumors/cancer are/is detected. However, the <it>CDK4 </it>IVS4-nt40 AA genotype is significantly associated with cancer and tumors/cancer in obese patients.</p> <p>Conclusion</p> <p>This finding is interesting since obesity is a risk factor for tumors and cancer. This study should prompt further work aiming at establishing the role of <it>CDK4 </it>in contributing to tumor/cancer genetic risk predisposition, as well as its role as a potentially effective therapeutic target gene for obesity-associated tumor/cancer management.</p

CHOP 5'UTR-c.279T>C and +nt30C>T variants are not associated with overweight condition or with tumors/cancer in Italians – a case-control study

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes (T2D) is associated with obesity and has been shown recently to be associated with tumors/cancer. <it>HNF1-beta </it>and <it>JAZF1 </it>genes are associated with T2D and prostate cancer. We have previously shown that <it>CHOP </it>5'UTR-c.279T>C and +nt30C>T haplotype variants contribute to T2D. CHOP deficiency causes obesity in mice, thus <it>CHOP </it>gene variants may contribute to human obesity. Furthermore, <it>CHOP </it>mediates apoptosis and is implicated in cancer pathogenesis. Hence, we aimed at identifying any potential association of <it>CHOP </it>5'UTR-c.279T>C and +nt30C>T genotypes and corresponding haplotypes with overweight condition/pre-obesity and tumors/cancer in an Italian dataset.</p> <p>Methods</p> <p>We recruited from Italy 45 overweight subjects (body mass index (BMI) ≥ 25) and 44 control subjects (BMI < 25) as well as 54 cases with at least one cancer or at least one tumor and 43 control subjects without tumors/cancer from the general population. We excluded allelic departure from Hardy-Weinberg equilibrium in cases and control subjects, separately.</p> <p>Results</p> <p>We assessed the power to detect risk odds ratios by association tests in our datasets. We tested the hypothesis of association of CHOP 5'UTR-c.279T>C and +nt30C>T genotypes and haplotypes with tumors/cancer and, separately, with overweight condition. Both associations were not significant.</p> <p>Conclusion</p> <p>From our study, we may conclude that <it>CHOP </it>5'UTR-c.279T>C and +nt30C>T genotypes and corresponding haplotypes are not associated with tumors/cancer and pre-obesity. However, more studies are warranted to establish the role of <it>CHOP </it>variants in tumor/cancer predisposition and in overweight condition.</p

Successful Medical Management of Status Post-Roux-en-Y-Gastric-Bypass Hyperinsulinemic Hypoglycemia

Roux-en-Y gastric bypass (RYGBP) is the most commonly performed type of bariatric surgery, which is used in the treatment of obesity and type 2 diabetes. Recent case reports and case series have described a rare complication of RYGBP, status post-gastric-bypass hyperinsulinemic hypoglycemia, which was mainly managed successfully with pancreatectomy. In this letter, we describe the first successful management of status post-gastric-bypass hyperinsulinemic hypoglycemia with diazoxide

Implication of Melanocortin Receptor Genes in the Familial Comorbidity of Type 2 Diabetes and Depression.

The melanocortin receptors are G-protein-coupled receptors, which are essential components of the hypothalamic–pituitary–adrenal axis, and they mediate the actions of melanocortins (melanocyte-stimulating hormones: α-MSH, β-MSH, and γ-MSH) as well as the adrenocorticotropin hormone (ACTH) in skin pigmentation, adrenal steroidogenesis, and stress response. Three melanocortin receptor genes (MC1R, MC2R, and MC5R) contribute to the risk of major depressive disorder (MDD), and one melanocortin receptor gene (MC4R) contributes to the risk of type 2 diabetes (T2D). MDD increases T2D risk in drug-naïve patients; thus, MDD and T2D commonly coexist. The five melanocortin receptor genes might confer risk for both disorders. However, they have never been investigated jointly to evaluate their potential contributing roles in the MDD-T2D comorbidity, specifically within families. In 212 Italian families with T2D and MDD, we tested 11 single nucleotide polymorphisms (SNPs) in the MC1R gene, 9 SNPs in MC2R, 3 SNPs in MC3R, 4 SNPs in MC4R, and 2 SNPs in MC5R. The testing used 2-point parametric linkage and linkage disequilibrium (LD) (i.e., association) analysis with four models (dominant with complete penetrance (D1), dominant with incomplete penetrance (D2), recessive with complete penetrance (R1), and recessive with incomplete penetrance (R2)). We detected significant (p ≤ 0.05) linkage and/or LD (i.e., association) to/with MDD for one SNP in MC2R (rs111734014) and one SNP in MC5R (rs2236700), and to/with T2D for three SNPs in MC1R (rs1805007 and rs201192930, and rs2228479), one SNP in MC2R (rs104894660), two SNPs in MC3R (rs3746619 and rs3827103), and one SNP in MC4R genes (Chr18-60372302). The linkage/LD/association was significant across different linkage patterns and different modes of inheritance. All reported variants are novel in MDD and T2D. This is the first study to report risk variants in MC1R, MC2R, and MC3R genes in T2D. MC2R and MC5R genes are replicated in MDD, with one novel variant each. Within our dataset, only the MC2R gene appears to confer risk for both MDD and T2D, albeit with different risk variants. To further clarity the role of the melanocortin receptor genes in MDD-T2D, these findings should be sought among other ethnicities as well

Comorbidity of Novel CRHR2 Gene Variants in Type 2 Diabetes and Depression

The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic-pituitary-adrenal stress response and to hyperglycemia and insulin resistance. CRHR2-/- mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association to/with depression (3 SNPs/D1, 2 SNPs/D2, 3 SNPs/R1, 3 SNPs/R2) and type 2 diabetes (3 SNPs/D1, 2 SNPs/D2, 2 SNPs/R1, 1 SNP/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying CRHR2 has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants\u27 dysfunction. CRHR2 is for the first time linked to/in linkage-disequilibrium/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy

Computational Identification of Gene Networks as a Biomarker of Neuroblastoma Risk

Neuroblastoma is a common cancer in children, affected by a number of genes that interact with each other through intricate but coordinated networks. Traditional approaches can only reconstruct a single regulatory network that is topologically not informative enough to explain the complexity of neuroblastoma risk. We implemented and modified an advanced model for recovering informative, omnidirectional, dynamic, and personalized networks (idopNetworks) from static gene expression data for neuroblastoma risk. We analyzed 3439 immune genes of neuroblastoma for 217 high-risk patients and 30 low-risk patients by which to reconstruct large patient-specific idopNetworks. By converting these networks into risk-specific representations, we found that the shift in patients from a low to high risk or from a high to low risk might be due to the reciprocal change of hub regulators. By altering the directions of regulation exerted by these hubs, it may be possible to reduce a high risk to a low risk. Results from a holistic, systems-oriented paradigm through idopNetworks can potentially enable oncologists to experimentally identify the biomarkers of neuroblastoma and other cancers