Some type 2 diabetes-associated SNPs identified by genome-wide association scans may act as cis-eQTL and increase disease susceptibility by modulating expression of nearby transcripts in human ...tissues.
Context:
Genome-wide association scans (GWAS) have identified novel single nucleotide polymorphisms (SNPs) that increase T2D susceptibility and indicated the role of nearby genes in T2D pathogenesis.
Objective:
We hypothesized that T2D-associated SNPs act as cis-regulators of nearby genes in human tissues and that expression of these transcripts may correlate with metabolic traits, including insulin sensitivity (SI).
Design, Settings, and Patients:
Association of SNPs with the expression of their nearest transcripts was tested in adipose and muscle from 168 healthy individuals who spanned a broad range of SI and body mass index (BMI) and in transformed lymphocytes (TLs). We tested correlations between the expression of these transcripts in adipose and muscle with metabolic traits. Utilizing allelic expression imbalance (AEI) analysis we examined the presence of other cis-regulators for those transcripts in TLs.
Results:
SNP rs9472138 was significantly (P = 0.037) associated with the expression of VEGFA in TLs while rs6698181 was detected as a cis-regulator for the PKN2 in muscle (P = 0.00027) and adipose (P = 0.018). Significant association was also observed for rs17036101 (P = 0.001) with expression of SYN2 in adipose of Caucasians. Among 19 GWAS-implicated transcripts, expression of VEGFA in adipose was correlated with BMI (r = −0.305) and SI (r = 0.230). Although only a minority of the T2D-associated SNPs were validated as cis-eQTLs for nearby transcripts, AEI analysis indicated presence of other cis-regulatory polymorphisms in 54% of these transcripts.
Conclusions:
Our study suggests that a small subset of GWAS-identified SNPs may increase T2D susceptibility by modulating expression of nearby transcripts in adipose or muscle.
Emerging infectious diseases (EIDs) pose an increasingly significant global burden, driven by urbanization, population explosion, global travel, changes in human behavior, and inadequate public ...health systems. The recent SARS-CoV-2 pandemic highlights the urgent need for innovative and robust technologies to effectively monitor newly emerging pathogens. Rapid identification, epidemiological surveillance, and transmission mitigation are crucial challenges for ensuring public health safety. Genomics has emerged as a pivotal tool in public health during pandemics, enabling the diagnosis, management, and prediction of infections, as well as the analysis and identification of cross-species interactions and the categorization of infectious agents. Recent advancements in high-throughput DNA sequencing tools have facilitated rapid and precise identification and characterization of emerging pathogens. This review article provides insights into the latest advances in various genomic techniques for pathogen detection and tracking and their applications in global outbreak surveillance. We assess methods that leverage pathogen sequences and explore the role of genomic analysis in understanding the epidemiology of newly emerged infectious diseases. Additionally, we address technical challenges and limitations, ethical and legal considerations, and highlight opportunities for integrating genomics with other surveillance approaches. By delving into the prospects and obstacles of genomics, we can gain valuable insights into its role in mitigating the threats posed by emerging pathogens and improving global preparedness in the face of future outbreaks.
The endoplasmic reticulum (ER) of adipocytes plays a major role in the assembly and secretion of adipokines. The levels of serum adiponectin, secreted by adipocytes, are decreased in insulin ...resistance, diabetes, and obesity. The role of ER stress in downregulating adiponectin levels has been demonstrated in mouse models of obesity. Studies examining human adipose tissue have indicated that there is an increase in the ER stress transcript HSPA5 with increased body mass index (BMI). However, it is not established whether ER stress results in changes in adiponectin levels or multimerization in human adipocytes. We examined whether the induction of ER stress using tunicamycin, thapsigargin, or palmitate alters the messenger RNA (mRNA) and protein expression of adiponectin and the mRNA expression of chaperones ERP44 and ERO1 in adult-derived human adipocyte stem (ADHAS) cells. ER stress was measured using key indicators of ER stress-HSPA5, ERN1, CHOP, and GADD34, as well as changes in eIF2α phosphorylation. Because ER stress is suggested to be the proximal cause of inflammation in adipocytes, we further examined the change in inflammatory status by quantitating the change in Iκβ-α protein following the induction of ER stress. Our studies indicate that: (1) ER stress markers were increased to a higher degree using tunicamycin or thapsigargin compared to palmitate; (2) ER stress significantly decreased adiponectin mRNA in response to tunicamycin and thapsigargin, but palmitate did not decrease adiponectin mRNA levels. In all three instances, the induction of ER stress was accompanied by a decrease in adiponectin protein as well as adiponectin multimerization. All three inducers of ER stress increased tumor necrosis factor-α (TNF-α) mRNA and decreased Iκβ-α protein in adipocytes. The data suggest that ER stress modifies adiponectin secretion and induces inflammation in ADHAS cells.
Recent studies indicate a stage-specific, differential role for the oncogene Akt on various cancers. In prostate cancer (PCa), suppression of Akt activity in the advanced stages promoted transforming ...growth factor-β (TGFβ) pathway-mediated epithelial-to-mesenchymal transition (EMT) and metastasis to the lungs. In the current study, we performed Affymetrix analysis to compare the expression profile of microRNAs in the mouse prostate tissues collected at the prostatic inter-epithelial neoplasia (PIN) stage from Transgenic adenocarcinoma of the mouse (TRAMP)/Akt1+/+ versus TRAMP/Akt1–/– mice, and at the advanced stage from TRAMP/Akt1+/+ mice treated with triciribine (Akt inhibitor) versus DMSO-treated control. Our analysis demonstrates that in the early stage, Akt1 in the TRAMP prostate tumors express a set of miRNAs responsible for regulating cancer cell survival, proliferation, and tumor growth, whereas, in the advanced stages, a different set of miRNAs that promote EMT and cancer metastasis is expressed. Our study has identified novel Akt-regulated signature microRNAs in the early and advanced PCa and demonstrates their differential effects on PCa growth and metastasis.
Complete remission (CR) in acute myeloid leukemia (AML) is defined as having ≤5% leukemic blast cells in the bone marrow and return of normal hematopoiesis after the first induction cycle. There is a ...subset of patients, however, who achieve reduction of leukemic blast cells with a subnormal platelet count, designated as CR with incomplete platelet recovery (platelet count, ≤100,000/mcL; normal, 150,000-450,000/mcL), which is associated with inferior outcomes when compared with CR. Furthermore, there is another subset of patients with CR but superior platelet counts (≥400,000/mcL) whose prognostic significance is unclear.
To establish whether CR with superior platelet counts is associated with better outcomes and can be used as a separate entity for prognostication.
A retrospective chart review of 104 cases of AML was conducted. The highest platelet count during days 25-35 from initiation of induction chemotherapy (designated as day 30 platelet count) was documented. A multivariate analysis for other factors such as age, sex, risk categories, day 14+ plasma cell count (average plasma cell percentage at days 14-21), infections, allogeneic bone marrow transplant, and remission status was done.
Day 30 platelet count was found to be an independent predictor of survival in AML. On the multivariate analysis, the subgroup with superior platelet counts (≥400,000/mcL) was found to be associated with better outcomes.
Results need to be validated in a larger cohort.
CR with superior platelet recovery (≥400,000/mcL) is a unique subcategory in itself and has prognostic significance. This may help better assess response to chemotherapeutic agents and aid in further decision-making regarding treatment.
Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately ...detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in nine patients, of which SVs in STK26 and DPP4 genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with interindividual variability in COVID-19 phenotypes.
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•Genetic predisposition studies remain limited to investigation of sequencing variants•We used optical genome mapping to investigate large SVs in severe COVID-19 patients•Identified seven rare SVs, with SVs in STK26 and DPP4 as the most promising candidates•Study highlights the potential role of SVs in the pathogenesis of COVID-19 severity
Genetic sample; Genomics; Virology
Abstract
Introduction: Next generation sequencing (NGS) based assays have revolutionized the field of genetic testing and paved their way into routine clinical practice. Owing to the complexity of ...the data, bioinformatics has become a necessary component for any laboratory implementing a clinical NGS test. However, there is an unmet need for accurate, efficient and standardized variant interpretation for actionable insights. In this effort, AMP/ASCO/CAP released a joint consensus recommendation proposing a four-tiered system to categorize somatic alterations based on their clinical significance in cancer diagnosis, prognosis, or therapeutics for standardization of interpretation and reporting of results among laboratories. Thus, the aim of the study was to assess and validate QIAGEN Clinical Insight (QCI) Interpret software for clinical laboratory test interpretation. Also, the AMP/ASCO/CAP guidelines were compared to an accredited laboratory approach for variant classification.
Patients and Methods: 87 BL-Q1 common and rare solid tumor cases were analyzed using the TrueSight170 NGS assay and secondary analysis platform (Illumina, San Diego, CA). The data was uploaded and analyzed using QCI Interpret. Patient case draft reports were produced using a TST170 customizable workflow with automated variant filtering, and variant classifications. Molecular geneticists compared the previous expert variant classification against the QCI Interpret computed AMP tier classification. Accuracy and specificity assessed as true positive, true negative, false positive and false negative rates were determined.
Results: Preliminary analysis on 52 cases with 496 alterations (SNVs, in-frame deletions, CNVs, fusions) resulted in 44 expertly classified alterations with strong therapeutic, prognostic, or diagnostic actionability (Tier I), 147 expertly classified alterations of potential therapeutic prognostic or diagnostic actionability (Tier II), and 304 variants of unknown clinical significance (Tier III). The QCI interpret computed classification yielded 44 Tier I (Strong clinical significance), 153 Tier II, 299 Tier III SNS2 variants. Expert and QCI Interpret computed Tier 1 classification are in 100% agreement. The accuracy for Tier II and Tier III classification were 96% (153 vs. 147) and 98% (299 vs. 304), respectively. However, the Manual interrogation of the 6 discrepant variants revealed that these were emerging biomarkers that were previously characterized as Tier III but due to recent biological evidence are now classified as Tier II.
Conclusion: Systematic evaluation of an automated classification based on AMP/ASCO/CAP using an up to date knowledge base is critical to accurately classify actionable mutations and detect emerging relevant mutations. The guidelines seem to yield results sufficiently good for clinical use and are a big step forward regarding standardization and use for classifying somatic alterations. The QCI Interpret seems to be a critical bioinformatics tool that adheres to the AMP/ASCO/CAP classification system and can be used across clinical laboratories for accurate, efficient and standardized variant interpretation for actionable insights.
Citation Format: Nikhil Sahajpal, Ashis Mondal, Meenakshi Ahluwalia, Allan Njau, Ravindra Kolhe. Validation of somatic variant interpretations from comprehensive cancer panels using QIAGEN Clinical Insight Interpret abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5482.
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