CNV Analysis Associates AKNAD1 with Type-2 Diabetes in Jordan Subpopulations.
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ABSTRACT:
SUBMITTER: Dajani R
PROVIDER: S-EPMC4543987 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The prevalence of Type II Diabetes (T2D) has been increasing and has become a disease of significant public health burden in Jordan. None of the previous genome-wide association studies (GWAS) have specifically investigated the Middle East populations. The Circassian and Chechen communities in Jordan represent unique populations that are genetically distinct from the Arab population and other populations in the Caucasus. Prevalence of T2D is very high in both the Circassian and Chechen communities in Jordan despite low obesity prevalence. We conducted GWAS on T2D in these two populations and further performed meta-analysis of the results. We identified a novel T2D locus at chr20p12.2 at genome-wide significance (rs6134031, P = 1.12 × 10-8) and we replicated the results in the Wellcome Trust Case Control Consortium (WTCCC) dataset. Another locus at chr12q24.31 is associated with T2D at suggestive significance level (top SNP rs4758690, P = 4.20 × 10-5) and it is a robust eQTL for the gene, MLXIP (P = 1.10 × 10-14), and is significantly associated with methylation level in MLXIP, the functions of which involves cellular glucose response. Therefore, in this first GWAS of T2D in Jordan subpopulations, we identified novel and unique susceptibility loci which may help inform the genetic underpinnings of T2D in other populations.
| S-EPMC5563445 | biostudies-literature
Project description:We aimed to characterize the type 2 diabetes mellitus (T2DM) epidemic and the role of key risk factors in Jordan between 1990-2050, and to forecast the T2DM-related costs. A recently-developed population-level T2DM mathematical model was adapted and applied to Jordan. The model was fitted to six population-based survey data collected between 1990 and 2017. T2DM prevalence was 14.0% in 1990, and projected to be 16.0% in 2020, and 20.6% in 2050. The total predicted number of T2DM cases were 218,326 (12,313 were new cases) in 1990, 702,326 (36,941 were new cases) in 2020, and 1.9 million (79,419 were new cases) in 2050. Out of Jordan's total health expenditure, 19.0% in 1990, 21.1% in 2020, and 25.2% in 2050 was forecasted to be spent on T2DM. The proportion of T2DM incident cases attributed to obesity was 55.6% in 1990, 59.5% in 2020, and 62.6% in 2050. Meanwhile, the combined contribution of smoking and physical inactivity hovered around 5% between 1990 and 2050. Jordan's T2DM epidemic is predicted to grow sizably in the next three decades, driven by population ageing and high and increasing obesity levels. The national strategy to prevent T2DM needs to be strengthened by focusing it on preventive interventions targeting T2DM and key risk factors.
| S-EPMC7713435 | biostudies-literature
Project description:BackgroundMicroarray technology allows the analysis of genomic aberrations at an ever increasing resolution, making functional interpretation of these vast amounts of data the main bottleneck in routine implementation of high resolution array platforms, and emphasising the need for a centralised and easy to use CNV data management and interpretation system.ResultsWe present CNV-WebStore, an online platform to streamline the processing and downstream interpretation of microarray data in a clinical context, tailored towards but not limited to the Illumina BeadArray platform. Provided analysis tools include CNV analsyis, parent of origin and uniparental disomy detection. Interpretation tools include data visualisation, gene prioritisation, automated PubMed searching, linking data to several genome browsers and annotation of CNVs based on several public databases. Finally a module is provided for uniform reporting of results.ConclusionCNV-WebStore is able to present copy number data in an intuitive way to both lab technicians and clinicians, making it a useful tool in daily clinical practice.
| S-EPMC3024943 | biostudies-literature
Project description:T- and B-lymphocytes play an important role in the pathogenesis of type 1 diabetes (T1D), a chronic disease caused by the autoimmune destruction of the insulin-producing cells in the pancreatic islets. Flow cytometry allows their characterization in peripheral blood, letting to investigate changes in cellular subpopulations that can provide insights in T1D pathophysiology. With this purpose, CD4+ and CD8+ T cells (including naïve, central memory, effector memory and terminally differentiated effector (TEMRA), Th17 and Tregs) and B cells subsets (naïve, unswitched memory, switched memory and transitional B cells) were analysed in peripheral blood of adult T1D patients at disease onset and after ≥2 years using multiparametric flow cytometry. Here we report changes in the percentage of early and late effector memory CD4+ and CD8+ T cells as well as of naïve subsets, regulatory T cells and transitional B cells in peripheral blood of adult patients at onset of T1D when compared with HD. After 2 years follow-up these changes were maintained. Also, we found a decrease in percentage of Th17 and numbers of T cells with baseline. In order to identify potential biomarkers of disease, ROC curves were performed being late EM CD4 T cell subset the most promising candidate. In conclusion, the observed changes in the percentage and/or absolute number of lymphocyte subpopulations of adult T1D patients support the hypothesis that effector cells migrate to the pancreas and this autoimmune process perseveres along the disease. Moreover, multiparametric flow allows to identify those subsets with potential to be considered biomarkers of disease.
| S-EPMC8685245 | biostudies-literature
Project description:BackgroundAssessing the prevalence and progression of hypertension among diabetics is crucial for designing appropriate strategies for successfully managing hypertension and its life-threatening complications. This study aimed to assess the prevalence of hypertension, its progression, and its determinants among type 2 diabetes mellitus (T2DM) patients in Jordan.Materials and methodsA cross-sectional study was conducted among 1382 Jordanian patients with T2DM in the period from January 2019 to January 2020. Blood pressure (BP) was followed and measured every 2-3 months using standardized automated sphygmomanometer during patients' routine visits for a total of 12 months. Data were obtained from medical records that included sociodemographic variables, anthropometric measurements, HbA1c, lipid profile, presence of T2DM complications and treatment.ResultsThe prevalence of hypertension among T2DM patients at the baseline was 74.6% (95% CI: 72.2%, 76.9%). The one-year incidence of hypertension among T2DM patients who were free of hypertension at the baseline was 26.2% (95% CI: 21.7%, 31.1%). In the multiple logistics regression analysis, patients older than 60 years (OR = 1.3 (95% CI: 1.01, 1.7); p-value 0.045) and those with positive family history of hypertension (OR = 4.2 (95% CI: 1.2, 8.2); p-value 0.026) were more likely to have uncontrolled hypertension. Patients who were using insulin only were less likely (OR = 0.5 (95% CI: 0.2, 0.9); p-value 0.026) to have uncontrolled hypertension compared to those who were on oral hypoglycemic agents only.ConclusionThe prevalence of hypertension among Jordanian patients with T2DM is alarmingly high. Healthcare providers should be committed to policies or preventive strategies targeting the modifiable risk factors associated with hypertension.
| S-EPMC8666513 | biostudies-literature
Project description:Sex and genetic variation influence the risk of developing diabetic nephropathy and ESRD in patients with type 1 diabetes. We performed a genome-wide association study in a cohort of 3652 patients from the Finnish Diabetic Nephropathy (FinnDiane) Study with type 1 diabetes to determine whether sex-specific genetic risk factors for ESRD exist. A common variant, rs4972593 on chromosome 2q31.1, was associated with ESRD in women (P<5×10(-8)) but not in men (P=0.77). This association was replicated in the meta-analysis of three independent type 1 diabetes cohorts (P=0.02) and remained significant for women (P<5×10(-8); odds ratio, 1.81 [95% confidence interval, 1.47 to 2.24]) upon combined meta-analysis of the discovery and replication cohorts. rs4972593 is located between the genes that code for the Sp3 transcription factor, which interacts directly with estrogen receptor ? and regulates the expression of genes linked to glomerular function and the pathogenesis of nephropathy, and the CDCA7 transcription factor, which regulates cell proliferation. Further examination revealed potential transcription factor-binding sites within rs4972593 and predicted eight estrogen-responsive elements within 5 kb of this locus. Moreover, we found sex-specific differences in the glomerular expression levels of SP3 (P=0.004). Overall, these results suggest that rs4972593 is a sex-specific genetic variant associated with ESRD in patients with type 1 diabetes and may underlie the sex-specific protection against ESRD.
| S-EPMC3785274 | biostudies-literature
Project description:We investigated the relationships between cerebral blood flow (CBF), cognitive, and mobility decline in type 2 diabetes mellitus (T2DM) over a 2-year period. Seventy-three participants (41 T2DM and 32 controls) were evaluated using volumetric CBF with arterial spin labeling perfusion magnetic resonance imaging at baseline and at the 2-year follow-up. Regions with significant CBF differences between T2DM participants and controls at baseline were detected using voxel-wise analysis. Correlation analysis was performed to investigate the association between regional CBF and cognitive or mobility performance over the 2-year span. Compared to controls, participants with T2DM had decreased CBF in the resting-state default mode, visual, and cerebellum networks. Greater decrease in longitudinal CBF values at these regions over a 2-year span was associated with worse gait, memory and executive functions, and higher baseline insulin resistance and worse baseline cognitive performance. In T2DM, impairment of resting regional perfusion is closely related to worse cognitive and mobility performance. Insulin resistance may further contribute to regional perfusion deficit in T2DM.
| S-EPMC5687828 | biostudies-other
Project description:Abstract Genetic variations of the dipeptidyl peptidase 4 enzyme (DPP-4) have been associated with glycemic disorders, especially among older adults. The objective of this study was to investigate the association of a single nucleotide polymorphism on the DPP4 gene with the occurrence of type 2 diabetes mellitus in a sample of older community-dwelling patients. Clinical, anthropometric and physiological characteristics as well as biochemical data related to lipidemia, glycemia and hormonal factors and variables related to the lifestyle were analyzed among 338 individuals aged 60 years and older from two general geriatric outpatient clinics in the Federal District, Brazil. Genotypes related to the polymorphism rs3788979 (A/G) of the DPP4 gene of these patients were determined by conventional polymerase chain reaction followed by enzymatic restriction, whereas the serum levels of DPP-4 were assessed by colorimetric immunoassay. Among the results obtained, there was clear variation in the glycemic levels both in terms of blood glucose and glycosylated hemoglobin according to DPP-4 genotypes, with increased levels between homozygotes for the G allele. However, no association was found between genotypes and occurrence of type 2 diabetes mellitus in patients. No other clinical, biochemical or anthropometric variables were influenced by the polymorphism. In our conditions, there was no association between genotypes and DPP-4 levels. Considering that DPP-4 is involved in the metabolism of incretins and directly interferes with glycemia in organisms, our result corroborates that genetic variations of this enzyme can affect glycemic homeostasis, despite not being determinant for the occurrence of type 2 diabetes mellitus.
| S-EPMC7740615 | biostudies-literature
Project description:The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance. Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.
| S-EPMC8580990 | biostudies-literature
Project description:Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.
| S-EPMC7410084 | biostudies-literature