3613 results for "*geneti*"

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• Type 1 Diabetes TrialNet

  Type 1 Diabetes TrialNet (TrialNet) is an international network of researchers established in 2003 for the purpose of conducting studies designed to evaluate new approaches to prevent, delay and reverse the progression of type 1 diabetes. These include interventions designed to decrease β-cell destruction and/or enhance β-cell survival. TrialNet engages in new onset diabetes trials to assess safety and to determine whether interventions can lead to preservation of C-peptide. Positive results from new onset trials are then evaluated as to whether the intervention can be brought into the prevention space for further evaluation. Other TrialNet goals include characterization of diabetes risk and pathophysiology through genetic, immunologic, and metabolic studies in participants participating in clinical studies. TN01 Bulk mRNA – RNA Sequencing The TrialNet “Key Question 1” study investigates immune system alterations associated with Type 1 Diabetes (T1D) progression using a retrospective, longitudinal nested case-control approach. It analyzes immune phenotype and gene expression changes in 178 individuals (89 cases, 89 controls). Cases include islet autoantibody-positive individuals from the TN01 Pathway to Prevention trial who developed T1D within a three year observation period, while controls are non-progressors matched by age, sex, and sampling timepoints. Serial blood samples were collected over three years, from pre-T1D to clinical diagnosis. Analyses include mass cytometry and transcriptomics. The RNA Sequencing portion of the study examines gene expression in five purified immune cell types: CD4+ T memory cells, CD8+ T memory cells, CD4+ T regulatory (Treg) memory cells, CD19+ B memory cells, and Natural Killer (NK) cells. RNA sequencing, with spike-in control RNA (ERCC), is used to control for batch variation. Whole Blood Genotyping – ExomeChip DNA from whole blood samples from TrialNet study participants was obtained and used for genotyping. Individuals included participants from TN01 Pathway to Prevention study and the following interventional trials: TN07 Oral Insulin, TN10 Anti-CD3 Prevention, TN18 Abatacept Prevention, TN20 Immune Effects of Oral Insulin, and TN22 Hydroxychloroquine Prevention. All interventional trial participants originated from TN01 Pathway to Prevention. Genotyping was performed by the University of Virginia using the Illumina TEDDY-T1DExome array. The TEDDY-T1DExome array is a custom chip that contains 550,601 markers from the Infinium CoreExome-24 v1.1 BeadChip and an additional 90,214 tagSNPs specifically selected by the TEDDY investigators based on their associations with nutrients, vitamins, type 2 diabetes, autoimmune diseases, body-mass index, or other exposures and phenotypes measured by TEDDY study. The Illumina GenTrain2 algorithm was used for genotype calling. Sample quality control metrics included sample call rate, heterozygosity rate and concordance of gender between the information reported and genotyped.

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• Cryptococcosis in Previously Healthy Adults

  Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients and is currently responsible for an estimated 15% of all AIDS-related deaths globally. However, in developed countries, approximately one-third of cases fall outside these groups such that cryptococcal meningoencephalitis (CM) has become the most common cause of non-viral meningitis in the U.S. Within the U.S., approximately 15-20% have no readily identifiable immune defect and cryptococcal infection in these hosts has a mortality rate of 30-50% despite optimal antifungal therapy. NIH Clinical Study Protocol 93-I-0106 (NCT00001352). The objectives of this protocol can be broadly categorized as: 1) Characterize the immunologic and genetic mechanisms predisposing to disease acquisition; 2) Understand the post-infectious inflammatory response and distinguish its consequences from those directly due to fungal growth; and 3) Management of post-infectious neuro-inflammatory syndromes associated with cryptococcal meningitis (CM). This protocol recruits patients who have microbiological evidence of cryptococcal neurologic or non-CNS disease (typically pulmonary or bone). Cerebrospinal fluid (CSF) and blood samples collected during clinical care are used to measure serum and CNS cellular and soluble cytokines as well as to perform in-situ immunohistochemistry. CSF and blood samples are also collected to measure transcriptional (gene expression), proteomic (protein), and lipidomic (lipids) changes that occur throughout disease and treatment. Observational data detailing audiological, ophthalmological and neurocognitive deficits in these patients is also recorded. We have recently described a post-infectious inflammatory syndrome (PIIRS) associated with cryptococcal meningoencephalitis (CM) which can be best described as a neuro-inflammatory state during which CM patients present with altered mental status (Montreal Cognitive Assessment Score As part of the protocol, we treat patients for either microbiological failure or neuroinflammatory sequelae by conventional therapies utilizing FDA-approved pharmaceuticals at FDA-approved doses. To understand and identify the predominant biological pathways responsible for PIIRS neuroinflammation, we examined patient CSF at baseline (at time of PIIRS diagnosis) and post-treatment with different FDA-approved pharmaceuticals at FDA-approved doses compared to CSF from non-PIIRS donors. Upstream pathway analysis of differentially expressed genes in the CSF of PIIRS patients revealed a prominent role for the JAK/STAT pathway in the pathogenesis of PIIRS and support the use of the JAK inhibitor, ruxolinib, as a pathway-instructed therapy to treat PIIRS patients. Data available through dbGaP: single cell RNA sequencing (scRNA-seq) data from CSF cells of a patient with PIIRS at the time of diagnosis and following treatment with steroids (1g solumedrol/day) and NanoString transcriptional data from CSF cells of patients with PIIRS at the time of diagnosis compared to CSF cells from non-PIIRS donors.

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• Genetic and Epigenetic Screens in Primary Human T Cells Link Candidate Causal Autoimmune Variants to T Cell Networks

  We aimed to define the target genes and pathways in which autoimmune disease-associated genetic variants operate. We performed single cell-CRISPR-interference screens in primary human T cells and bulk RNA-seq on T cells containing CRISPRi and single gRNAs to assess how T cell regulatory regions containing autoimmune-associated genetic variants affect nearby gene expression and cellular programs.

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• Prostate Cancer Upgrading Reference Set

  This study aimed to investigate clinical, demographic, and molecular features of men diagnosed with low-risk prostate cancer [ISUP Grade Group 1 (GG1)] at biopsy who underwent radical prostatectomy, and for whom an increased tumor grade (ISUP Grade Group 2 or above) was subsequently detected in the resected prostate. This phenomenon is termed upgrading. In collaboration with the Early Detection Research Network (EDRN), a blinded reference set was established to facilitate upgrading biomarker detection and validation. A prospective, multi-institutional, cohort of men with the GG1 prostate cancer and intention to undergo prostatectomy was recruited. Biospecimens (blood, urine) were collected and this biorepository comprises the official EDRN Upgrading Reference Set (URS). Recording of case-control status (case = upgrading at prostatectomy, control = no upgrading at prostatectomy) was coordinated by the Data Management and Coordinating Center (DMCC) of the EDRN, who ensured blinding of all participating researchers. A subset of the reference set (n = 192) was chosen to undergo whole genome sequencing (WGS) for the investigation of a germline genomic biomarker of upgrading. Variant calls from all sequenced URS whole genomes are available through dbGaP, with the exception of one sample for which sequencing was not successful. Among investigated clinical features, prostate-specific antigen (PSA) density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. Two polygenic risk score-based biomarkers were computed in the genetic sub-cohort and tested against case-control status. Neither was predictive of upgrading.

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• Cystic Kidney Disease: Disease Spectrum and Genotype-Phenotype Correlations

  This study seeks to characterize the genetic landscape of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Sequencing data is primarily derived from a short-read targeted-Next Generation Sequencing (tNGS) custom panel of known and candidate genes towards polycystic kidney/liver diseases and ciliopathies. To understand the severity of the disease in individual patients, we have provided relevant phenotype information when available. This study is part of a multi-year effort; all submissions will be tied to this overarching dbGaP study to ensure continuity and facilitate integrated data access. Version 1 contains the tNGS sequencing data (BAM, gVCF, VCF) of Mayo Clinic patients with cystic kidney and/or cystic liver disease that were either negative for PKD1 or PKD2 pathogenic changes but had pathogenic changes detected in one of the minor ADPKD genes, such as IFT140, DNAJB11, ALG8, or ALG9. These individuals have been featured in publications detailing with monoallelic variants in these genes. The PubMed IDs are 39899384, 34890546, 29706351, and 32631624. Version 2 contains all data from Version 1. Version 2 additionally contains the tNGS sequencing data (BAM, gVCF, VCF) of Mayo Clinic patients with cystic kidney and/or cystic liver disease with pathogenic changes linked to NEK8 ADPKD and biallelic C2CD3 ciliopathy-based disorder. In addition, a pediatric cohort of cystic kidney-affected individuals as well as an Adult-Onset ARPKD phenotype cohort of individuals are featured in this version. These individuals have been featured in publications with respect to the phenotype and cohort group. The PubMed IDs are 41790507, 37598857, and 30097616. Subjects in the Adult-Onset ARPKD phenotype group are currently undergoing publication and this study will be updated to reflect this.

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• Multicenter Hemophilia Cohort Studies (MHCS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from MHCS include DNA, Peripheral Blood Mononuclear Cells, Plasma, Red Blood Cells, and Serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The First Multicenter Hemophilia Cohort Study (MHCS-I) evaluated and prospectively followed patients with hemophilia or a related coagulation disorder. Initiated in 1982, this study particularly sought to understand the cause and natural history of HIV infection and AIDS in this population which was at high risk for development of AIDS. The Second Multicenter Hemophilia Cohort Study (MHCS-II) evaluated and prospectively followed a cohort of subjects with hemophilia who were exposed to hepatitis C virus (HCV). The primary objectives were to quantify the rates of liver decompensation, hepatocellular carcinoma, and non-Hodgkin lymphoma and to evaluate candidate clinical, genetic, virologic, serologic and immunologic markers that are likely to be on the causal pathway for these conditions, identify predictive clinical and laboratory markers and follow the markers over time, identify host genes that confer susceptibility or resistance to HCV and HIV infections or to the diseases that result from these infections and to identify response and complication rates of various anti-HCV and anti-HIV regimens in the setting of comprehensive clinical care of persons with hemophilia. Background Treatment of hemophilia patients with contaminated plasma products before 1990 resulted in extraordinary prevalence rates of human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV, HCV). The first cases of acquired immunodeficiency syndrome (AIDS) were reported in the United States in 1981 and the first cases of AIDS in hemophilia patients were reported one year later. In contrast to HIV-1, HBV, HCV were present in the human population and HBV and HCV were almost certainly was always a contaminant of blood and plasma donated for transfusion prior to the development of diagnostic tests to screen blood donors. Participants Adults and children who had a congenital coagulation disorder [hemophilia A or B (congenital factor VIII or IX deficiency)] von Willebrand's disease, or other were enrolled from 8 collaborating hemophilia centers in the US between 1982 and 1985. Four additional centers from the US and 4 centers from Europe joined the study between 1987 and 1990. In MHCS-II, 52 collaborating hemophilia centers in North and South America and Europe, enrolled patients who had a congenital coagulation disorder [hemophilia A or B (congenital factor VIII or IX deficiency), von Willebrand's disease, or other], who had reached 13 years of age, and who had serological or molecular evidence of HCV or HIV-1 infection. The majority of subjects consisted of a "HCV cohort" of whom a portion was co-infected with HIV, the "HIV cohort". Design In MHCS-I, subjects were evaluated semiannually with a standardized physical examination, abstraction of medical records, and phlebotomy. In MHCS-II, The natural time scale was used, beginning with the estimated date of HCV or HIV infection to an event of interest, death, or censoring. Time initiated on the estimated date of HCV infection (HCV cohort) or HIV infection (HIV cohort) but follow-up was defined as the date of the first blood sample collected for the MHCS-I or -II. The main outcomes were liver decompensation, hepatocellular carcinoma and non-Hodgkin lymphoma. Measures included HCV viral load, anti-HCV levels and other markers of the primary outcomes such as serum cholesterol and inflammatory cytokine levels; host genetic polymorphism. Conclusions Nearly one-third of the MHCS-II participants were infected with HIV-1, many of whom were infected in childhood and all of whom have survived with HIV-1 for more than 15 years. As survivors, relatively few of them had an AIDS-defining opportunistic infection or malignancy (17%) or laboratory-defined AIDS. In contrast to use of HAART for HIV-1 infection, only a minority of MHCS-II participants had been treated for their HCV infection. In the MHCS-II cohort of HCV-seropositive people with hemophilia and related coagulation disorders, the prevalence rates of ascites, hepatomegaly, splenomegaly and persistent jaundice were 2- to 3-fold higher with HIV-1, when adjusted for age and most could not be ascribed to HAART or other anti-HIV-1 regimens. In the MHCS-II, 74% of the HIV-1-positive and 51% of the HIV-1-negative participants had evidence of current or previous HBV infection. In MHCS-I, the risk of decompensated end stage liver disease was increased 8.1-fold for carriers of hepatitis B surface antigen (HBsAg) and 3.4-fold for the much larger group of hemophiliacs who had cleared HBsAg. Publications Melendez-Morales L, Konkle BA, Preiss L, Zhang M, Mathew P, Eyster ME, Goedert JJ. Chronic hepatitis B and other correlates of spontaneous clearance of hepatitis C virus among HIV-infected people with hemophilia. AIDS. 2007; 21(12):1631-6. Goedert JJ; Second Multicenter Hemophilia Cohort Study. Prevalence of conditions associated with human immunodeficiency and hepatitis virus infections among persons with haemophilia, 2001-2003. Haemophilia. 2005; 11(5):516-28. Engels EA, Frisch M, Lubin JH, Gail MH, Biggar RJ, Goedert JJ. Prevalence of hepatitis C virus infection and risk for hepatocellular carcinoma and non-Hodgkin lymphoma in AIDS. J Acquir Immune Defic Syndr. 2002; 31(5):536-41. Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC 2nd, Angiolillo AL, Luban NL, Sherman KE, Manco-Johnson M, Preiss L, Leissinger C, Kessler CM, Cohen AR, DiMichele D, Hilgartner MW, Aledort LM, Kroner BL, Rosenberg PS, Hatzakis A. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood. 2002; 100(5):1584-9. O'Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen AR, Luban N, Hatzakis A, Aledort LM, Rosenberg PS, Miley WJ, Kroner BL, Goedert JJ. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study. JAMA. 1996; 276(2):105-10. Ehmann WC, Eyster ME, Wilson SE, Andes WA, Goedert JJ. Relationship of CD4 lymphocyte counts to survival in a cohort of hemophiliacs infected with HIV. Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr. 1994;7(10):1095-8. Goedert JJ, Cohen AR, Kessler CM, Eichinger S, Seremetis SV, Rabkin CS, Yellin FJ, Rosenberg PS, Aledort LM. Risks of immunodeficiency, AIDS, and death related to purity of factor VIII concentrate. Multicenter Hemophilia Cohort Study. Lancet. 1994; 344(8925):791-2. Erratum in: Lancet 1994; 344(8931):1238. Eyster ME, Fried MW, Di Bisceglie AM, Goedert JJ. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study. Blood. 1994; 84(4):1020-3. Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC 2nd, Drummond JE, Vaidya K, Mann DL, Eyster ME, et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med.1989; 321(17):1141-8. Lozier JN, Rosenberg PS, Goedert JJ, Menashe I. (2011), A case–control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A. Haemophilia, 17: no. doi: 10.1111/j.1365-2516.2010.02473.x

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• Next Generation Sequencing to Predict Risk of Events from Coronary Artery Disease

  Coronary artery disease (CAD) and myocardial infarction (MI) remain the leading cause of death worldwide and in the US. In recent years, clinical studies that considered intermediate phenotypes (phenotypic or genomic data isolated between DNA and the main disease phenotype) have greatly enhanced our understanding of complex traits like CAD by enabling inference of biological networks from the combination of genetic and genomic datasets isolated from disease-relevant tissue(s). The NGS-PREDICT study used whole transcriptome sequence data generated from primary macrophages derived in vitro from venous blood that was obtained from CAD cases and non-CAD controls. This study provided a valuable resource for the validation of biomarkers identified in STARNET NGS data from macrophages obtained from patients with and without CAD. It also can be used as a reference dataset for the study of metabolic syndrome as well as other systemic inflammatory diseases.

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• Platinum Pedigree Consortium Long-Read Sequencing

  Platinum Pedigree Consortium includes whole genome sequencing of blood-derived DNA using five technologies on a 4-generation family. This is the CEPH-Utah (CEU) family 1463 and includes 4 grandparents from 1st generation, 2 parents from 2nd generation, 5 children from 3rd generation, 9 individuals from the 4th generation representing 2 branches of the 3rd generation, and their 2 additional parents. Family was not selected for disease, rather large size to study genetic transmission and human variation.Data available through dbGaP include raw sequence data: PacBio HiFi reads in unaligned BAM formats, Ultra-Long Oxford Nanopore (ONT) reads in FASTQ formats, Illumina sequencing, strand-seq and Element sequencing data in FASTQ format. Additionally, alignment files for HiFi reads mapped to the GRCh38 and CHM13v2.0 reference genomes, as well as de novo genome assemblies generated for this project are included.

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• TET2 Loss Triggers ssDNA Gap Accumulation and Heightened PARP Inhibitor Sensitivity

  Here we sought to understand the molecular effects of TET2 knock out (KO) in U2OS cells. TET2 catalyzes the conversion of 5-methyl-cytosine to 5-hydroxy-methyl-cytosine (5hmC). We thus mapped 5hmC genome-wide using bACE-seq (bisulfite APOBEC-coupled epigenetic sequencing) in TET2 wild-type (WT) and KO. TET2 KO U2OS cells were engineered to remove ~42kb of TET2. TET2 KO was confirmed by PCR, western blot, and sequencing. bACE-seq analysis was then performed on genomic DNA isolated from three independent plates of WT and KO U2OS cells. Our subsequent analysis identified 4182 differentially hypo-hydroxy-methylated regions (hypo-hDMRs) and 651 hyper-hydroxy-methylated DMRs, confirming an overall reduction in the genomic levels of cytosine hydroxy-methylation upon TET2 loss. Hypo-hDMRs were spread across the chromosomes, and we did not observe specific chromosomal regions having preferential hDMR concentration. Moreover, we did not observe localization of hDMRs to any specific genomic compartment such as promoters, enhancers, or UTRs. Using previously published replication initiation and termination zones defined by OK-seq we observed that in WT cells initiation zones showed a slight reduction in 5hmC levels relative to randomized genomic control regions and termination zones. In TET2 KO cells, the difference at initiation zones was dampened as likely all genomic regions have reduced 5hmC. Here we provide bACE-seq hmC mapping data for TET2 WT and KO U2OS cells for three replicates of each condition.

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• Genome-Wide Association Study of the Taste and Hedonic Ratings of the Low-Calorie Sweetener Acesulfame Potassium

  Acesulfame potassium (Ace-K) is a low-calorie sweetener (LCS) widely used as an additive in foods and beverages and an excipient in pediatric medicines. Because genetic variants play a role in individual variation in the taste of Ace-K, we sought to identify genetic contributions to its taste using a genome-wide association study (GWAS). 141 adult panelists rated the taste of an aqueous solution of Ace-K using the general labelled magnitude scale (gLMS) and its palatability using the hedonic gLMS. Genotypes were assayed on the Infinium Global Screening Array. Imputation of genotypes was performed on the Michigan Imputation Server with 1000 Genomes Project phase 3 genotype data as reference. Linear regression was performed to test genetic associations between genotyped and imputed variants with three gLMS ratings (bitterness (square-root-transformed), hedonic, sweetness) of Ace-K using PLINK2, adjusting for standardized age, sex, and the first 10 principal components of genetic ancestry. We identified that a locus spanning several TAS2R (Taste receptor 2) genes was associated with bitterness ratings of Ace-K and a locus within the gene ELMO1 (Engulfment and Cell Motility Protein 1) was associated with hedonic ratings of Ace-K (p-values 40594245).

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