3613 results for "*geneti*"

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• Wnt Activity Reveals Context-Dependent Genetic Effects on Gene Regulation in Neural Progenitors

  In this study we aimed to identify context-dependent regulatory functions of common genetic variation after stimulation of the canonical Wnt pathway. Fetal cortical tissue between 14 and 21 gestation weeks was subjected to RNA-Sequencing (242 samples) and ATAC-Sequencing (222 samples) to profile expression and chromatin accessibility, respectively. Considering donor genotypes, we were able to identify eQTLs, caQTLs, as well as response QTLs of both categories. The dataset provided here includes 242 RNA-sequencing files in bam format and 222 ATAC-sequencing files in bam format. We also provide 83 donor genotypes in VCF format (hg38).

  Study phs003642

• Interdisciplinary Approaches for Understanding how Arsenic and Micronutrients Affect the Epigenome to Influence Spina Bifida Risk

  This hospital-based case-control study was conducted in Bangladesh between December 2016 and December 2022 to investigate the association between environmental arsenic exposure and the risk of spina bifida. The study enrolled children with spina bifida (cases) and unaffected children (controls), along with their biological parents. Cases included infants under one year of age with clinically confirmed diagnoses of myelomeningocele or meningocele at the National Institute of Neurosciences & Hospital (NINS). Controls were frequency-matched on age and recruited from the same catchment area through NINS and Dhaka Shishu Hospital. Children with conditions potentially related to arsenic exposure, such as keratosis or cancer, were excluded from the control group. A small subset of case families were reclassified as controls following surgical reevaluation and a revised diagnosis of lipomeningocele, then later removed from the control group. They are no longer assigned to either the case or control category in the datasets. Saliva samples were collected from children and parents using Oragene® kits and stored at room temperature before shipment to Boston, MA, USA. DNA extraction was carried out with the Maxwell® RSC Buccal Swab DNA kit. A total of 749 saliva DNA samples, representing 713 unique individuals and 36 replicates, were shipped to the Broad Institute for analysis. Samples were randomized across Illumina Global Screening Array (GSA) chips to minimize batch effects. The primary molecular technology employed in this study was the Illumina Global Screening Array (GSAMD-24v1-0), which includes approximately 688,000 genetic markers. Data generated include raw and processed genotype files as well as a comprehensive quality control report. The genotyping dataset available through dbGaP will consist of genotype calls from spina bifida cases, controls, and their parents, along with associated demographic, clinical, and exposure metadata, enabling future analyses of gene-environment interactions in the context of neural tube defect risk.

  Study phs003733

• Identifying the Genetic Basis of Variably Protease-Sensitive Prionopathy (VPSPr)

  Design: Sequencing of cases onlyMolecular technologies: Exome sequencing and custom targeted sequencing of PRNPAims: Identify modestly penetrant, high odds ratio variants conferring risk of variably protease-sensitive prionopathy (VPSPr)Population: n=67 autopsy-confirmed VPSPr cases, United States, 1997-2021Principal findings: Association to PRNP M129V replicated, no other causal variants identifiedData available: Raw sequencing data and metadata

  Study phs004012

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-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 PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants compared with placebo.Background: Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis participants experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in participants with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for participants with sepsis and respiratory or circulatory organ dysfunction. Participants: A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.Design: ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.Participants randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was Conclusions: Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

  Study phs003900

• AsthmaNet Best African American Response to Asthma Drugs (BARD-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. Objectives: To assess whether patients of African American heritage with inadequately controlled asthma benefit from the addition of a long-acting beta-agonist and/or increased glucocorticoids dosage, and whether the response varies for children vs. adolescents and adults.Background: Epidemiologic studies have demonstrated that African American patients with asthma experience more complications including exacerbations, asthma-related urgent-care visits, hospitalizations, and deaths, as compared to Caucasian patients with asthma. Ethnicity can also influence medication response, and studies have shown that African Americans patients have more glucocorticoid resistance, less cellular sensitivity to glucocorticoids, and more eosinophilic inflammation during inhaled glucocorticoid treatment than Caucasian patients. This may be due to the effect of genetic variants on response to pharmacotherapy for asthma.Asthma symptoms are primarily controlled with inhaled glucocorticoids, but a long-acting β2-adrenergic receptor agonist (LABA) may be used as an additional treatment when glucocorticoids alone do not sufficiently suppress symptoms. However, prior to the BARD study, this recommendation was based on studies with limited numbers of African American patients and without evaluation of differences in genetic ancestry. In particular, additional analysis has indicated that adding a LABA was not superior to increasing the dose of an inhaled glucocorticoid in African American patients. Therefore, the BARD trials were initiated to address this gap in scientific understanding and determine a preferred pharmacotherapy strategy in African American children, adolescents, and adults.Participants: Eligible participants were recruited from nine AsthmaNet sites and consisted of asthma patients at least five years of age that had at least one African American grandparent. Participants were required to have a baseline forced expiratory volume in 1 second (FEV1) of at least 40% of the predicted value after bronchodilator use (four 90 μg puffs of albuterol) and a diagnosis of asthma, as confirmed by beta-agonist reversibility, a methacholine provocation concentration causing a 20% decrease in the FEV1 of 16 mg per milliliter or less, or an absolute difference in the percentage of the predicted FEV1 of at least 12 percentage points over two measurements documented within the previous year. The asthma must also be inadequately controlled (CT/c-ACT score A total of 280 children and 294 adolescents and adults were enrolled and underwent randomization.Design: BARD consisted of two prospective, randomized, double-blind trials. One trial involved children 5 to 11 years of age with four treatment groups: doubling the dose of an inhaled glucocorticoid (fluticasone propionate) to 100 μg twice daily; doubling the dose of fluticasone to 100 μg and adding a LABA (salmeterol) at a dose of 50 μg; quintupling the dose of fluticasone to 250 μg; or quintupling the dose of fluticasone to 250 μg and adding 50 μg of salmeterol. The other trial involved adolescents and adults 12 years of age or older with four treatment groups: adding twice-daily salmeterol at a dose of 50 μg to baseline twice-daily administration of fluticasone propionate at a dose of 100 μg; increasing the dose of fluticasone by a factor of 2.5 to 250 μg; quintupling the dose of fluticasone to 500 μg; or increasing the dose of fluticasone by a factor of 2.5 to 250 μg and adding 50 μg of salmeterol. The first step-up regimen differed between trials due to the lack of a low-dose inhaled glucocorticoid-LABA medication for children. The trials were otherwise identical in design and step-up dosing strategies.The run-in period consisted of treatment up to 10 weeks with an open-label low-dose inhaled glucocorticoid (50 μg of fluticasone propionate twice daily in children and 100 μg twice daily in adolescents and adults) in order to assess whether patients had inadequately controlled asthma prior to randomization. Eligible patients were then randomly assigned to the step-up treatment sequences, each lasting 14 weeks, in a four-way crossover design with add-on LABA, different strengths of increased doses of inhaled glucocorticoid, or an increased dose of inhaled glucocorticoid with LABA in dry-powder. The initial 2 weeks of each period were considered to be a washout period for the previous treatment and a wash-in period for the new regimen. The primary clinical outcome of each trial was a hierarchical composite measure that sequentially evaluated asthma exacerbations, asthma-control days, and lung function (percentage of the predicted FEV1) at the end of the 14-week treatment regimens to determine a differential response. Conclusions: In African American adolescents and adults with poorly controlled asthma, the addition of a LABA to inhaled glucocorticoid was more likely to produce superior responses than increasing the dose of an inhaled glucocorticoid. In contrast, almost half of the African American children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA.

  Study phs004585

• BIRC5 Upregulation Enhances DNMT3A-Mutant T-ALL Cell Survival and Pathogenesis

  The goal of this study was to determine how patients with T-ALL who have DNA methyltransferase 3 alpha (DNMT3A) mutations develop resistance to therapy. Since DNMT3A is a methyltransferase, we examined the effect of those mutations on epigenetic regulation using whole genome bisulfite sequencing (WGBS). We also assessed any changes in gene expression using RNA-sequencing. We found that T-ALL patients with DNMT3A mutations are resistant to apoptosis and some chemotherapies. WGBS showed that DNMT3A mutated patients clustered together by their epigenetic profile, which was associated with hypomethylation at TERT and HOX genes. RNA sequencing identified differences in JAK/STAT signaling.

  Study phs003623

• NHLBI TOPMed: Pulmonary Vascular Disease Phenomics Program (PVDOMICS)

  Pulmonary Vascular Diseases (PVD) are classified into 5 World Health Organization (WHO) groups using clinical presentation and hemodynamics. WHO 1 Pulmonary Arterial Hypertension (PAH) is rare with heritable [HPAH] known deleterious genetic variants associated with severe, progressive lethal disease, and disproportionately affects women. Little is known of the more common WHO 2-5, which have PVD related to heart, lung, blood and sleep (HLBS) diseases. Current classification and guidelines offer no PVD-specific therapy for WHO 2-5. They receive standard of care for their HLBS disease, although they suffer much higher mortality than their nonPVD HLBS counterparts. The NHLBI Pulmonary Vascular Disease OMICS (PVDOMICS) network was created to establish a deeply-characterized cohort of all PVD patients linked to biospecimens to develop new classifications by characteristics (phenomes) associated with mechanisms of pathogenesis using multi-omic studies. PVDOMICS is the most thoroughly phenotyped PAH cohort, and the only cohort to include all 5 WHO and nonPVD comparators [patients with HLBS diseases without PVD, and healthy controls)].All PVD and nonPVD comparator participants and healthy controls with blood samples were selected for sequencing in TOPMed.

  Study phs002451

• Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2-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 P2C2 include Serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The objective of this study was to determine the prevalence and natural history of pulmonary and cardiac complications associated with HIV infection in utero, in infancy, and during early childhood.Background: In 1982, a year after the discovery of AIDS in adults, cases were described in children. Subsequent cross-sectional and short term longitudinal studies indicated that pulmonary and cardiac diseases contributed significantly to morbidity and mortality in children infected with the human immunodeficiency virus. This study aimed to investigate this hypothesis in a long-term cohort study.Participants: Children were enrolled at 5 geographically separated centers in Houston, TX, USA; Boston, MA; New York, NY; and Los Angeles, CA. The cohort of participants included two groups. Group I was composed of infants and children with vertically transmitted HIV-infection over 28 days of age. Children in Group I must have been born after April 1, 1985 except where vertical transmission of HIV infection could be documented with reasonable medical certainty and be more than 28 days old. Group II was composed of fetuses and infants of mothers infected with HIV.Participants in group I included children who were likely to develop extensive disease during the course of the study and therefore provide the opportunity to study the full range of cardiovascular and pulmonary complications associated with vertically-transmitted HIV-infection in children. Group II provided the opportunity to determine the earliest features of infection in the fetus and longitudinally to follow these effects in the child. Since a proportion of infants in this group were not infected, they represented a control group for the infected infants. Children in group I (n=205) were a median of 22.9 months of age at enrollment (1.7-166 months) of which 11.7% had asymptomatic infection and 88.3% presented with symptomatic infection. Among 600 infants born to HIV-1–infected women, 432 (72.0 %) were enrolled while their mothers were pregnant and 168 (28.0 %) before 28 days post partum. Among 93 HIV-1–infected infants, 29 (31.2 %) were enrolled postnatally (median, 12 days; range, 1 to 28). Design: In this prospective natural history study, research was conducted on the response of the immature lung to Pneumocystis carinii and other opportunistic lung infections, as well as on the etiology and pathogenesis of lymphocytic pulmonary disorders. The types, incidence, course, outcome, and origin of cardiac disorders were also determined. In addition to the pulmonary and cardiovascular measurements, data on the effects of co-infection with other viruses, CMV and EBV, were obtained.Enrollment of participants began in May 1990 and continued through April 1993 in Group I and through January 1994 for Group II. The cohort was followed at specified intervals for an additional three years beyond the end of recruitment for clinical examination, cardiac, pulmonary, immunologic, and infectious studies and for intercurrent illnesses. Follow-up ranged from 2.5 to 6.6 years. Conclusions: Vertically-transmitted HIV-1 infection is associated with persistent cardiovascular abnormalities identifiable shortly after birth. Irrespective of their HIV-1 status, infants born to women infected with HIV-1 have significantly worse cardiac function than other infants, suggesting that the uterine environment has an important role in postnatal cardiovascular abnormalities.

  Study phs004322

• Leukemia Relapse via Genetic Immune Escape after Allogeneic Hematopoietic Cell Transplantation

  Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here we demonstrate, through a broad immunogenetic study, that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and responses to immunomodulatory strategies. These findings define new molecular modes of post-transplant leukemia escape contributing to relapse.The present dataset provides HLA peripheral blood and bone marrow samples supporting the genotyping studies performed for this research. This sample set originates from patients with acute myeloid leukemia or myelodysplastic syndromes receiving allogeneic hematopoietic cell transplantation and relapsing after transplant.

  Study phs003235

• Acute Respiratory Distress Network (ARDSNet) Studies 01 and 03 Lower Versus Higher Tidal Volume, Ketoconazole Treatment and Lisofylline Treatment (ARMA/KARMA/LARMA) (ARDSNet-ARMA/KARMA/LARMA-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. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ARMA/KARMA/LARMA include plasma, serum and urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The primary objective of the KARMA trial was to investigate the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS. The Ketoconazole arm of the study was later stopped due to an inability to show efficacy. Participants continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management. Background Participants suffering from ARDS are extremely ill, require mechanical ventilation and, despite improvements in medical care and technology, had a mortality rate as high as 50 percent. An excessive inflammatory response is characteristic of ALI of which ARDS represents the most severe end of the pathophysiologic spectrum. The inflammatory response includes increased numbers of neutrophils activated to produce cytokines, proteases, and reactive oxygen intermediates. Pulmonary injury may also be enhanced by alveolar and tissue macrophages as a producer of vasoactive substances, neutrophil chemoattractants, and procoagulant substances. Ketoconazole, a synthetic antifungal imidazole, also has anti-inflammatory activities and may inhibit neutrophil recruitment via several different pathways known to be involved in the development of ALI and ARDS. Lisofylline causes a marked decrease in the circulating levels of the major oxidizable species of free fatty acids and also inhibits proinflammatory intracellular signaling. Mechanical ventilation in participants with ALI and ARDS have traditionally used tidal volumes of 10 to 15 ml per kilogram of body weight. These large tidal volumes are often necessary to achieve normal partial pressure of arterial carbon dioxide and pH, but may induce inflammatory responses through disruption of pulmonary epithelium and endothelium. Mechanical ventilation at lower tidal volumes may reduce injurious lung stretch and decrease the inflammatory response. Participants The Ketoconazole and Lisofylline trials were designed as 2 x 2 factorials and included 220 participants in each trial. A total of 860 participants were randomized into the ventilator management trial. Participants enrolled in the Lisofylline or Ketoconozole studies had to be concurrently enrolled in the ventilator management study and were first randomized into a ventilator strategy and then to drug or placebo. Conclusions Ketoconazole was found to be safe but did not reduce mortality, duration of mechanical ventilation, or improve lung function. Lisofylline was also found to be safe and to have no beneficial effect for participants with ALI or ARDS. Ventilation at lower tidal volumes resulted in reduced mortality and an increase in the number of days without ventilator support. (PMIDs: 10789668, 11902249, 10793162).

  Study phs003734