3613 results for "*geneti*"

in 47.45 milliseconds.

• Clarification of Optimal Anticoagulation through Genetics (COAG) (COAG-BioLINCC)

  Objectives: The COAG trial tested whether genotype-guided dosing of warfarin improves anticoagulation control during the first 4 weeks of therapy when compared to clinical-guided dosing.Background: Warfarin is highly efficacious at preventing thromboembolism, a condition associated with substantial morbidity and mortality. Individuals taking warfarin require dosage adjustments to maintain a therapeutic international normalized ratio (INR), particularly at the beginning of therapy. Out of range INR can increase risk of thromboembolism, bleeding, and early discontinuation of a highly useful therapy. Genotype-guided dosing of warfarin may be a more effective way of dosing warfarin when compared to only using clinical information. Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. Prior to the COAG trial, the effectiveness of genotype-guided dosing of warfarin had been limited to small clinical trials or observational studies, with equivocal results. Therefore comparison of the two strategies was needed to determine if use of genetic information is more effective in warfarin dosing than using clinical information.Participants: Participants were adults initiating warfarin therapy with a target international normalized ratio (INR) of 2 to 3 and an expected duration of therapy of at least 1 month. Exclusion criteria included current warfarin use, prior warfarin therapy with a known stable dose, and abnormal baseline INR (off warfarin). A total of 1015 subjects were enrolled in the study.Design: The COAG study was a multicenter, double-blind, randomized trial that compared two approaches to guiding warfarin therapy initiation. Subjects were randomly assigned in a 1:1 ratio to a dosing strategy during the first 5 days of warfarin therapy. For each dosing strategy, a dose-initiation algorithm was used during the first 3 days of therapy, and a dose-revision algorithm was used on day 4, 5, or both. The algorithms for the genotype-guided dosing strategy included clinical variables and genotype data for CYP2C92, CYP2C93, and VKORC1. The algorithms for the clinically based dosing strategy included clinical variables only. If genotype information was not available for a patient in the genotype-guided dosing group before the administration of warfarin on any given day in the first 5 days, the clinical algorithm was used on that day.During the first 4 weeks of therapy, patients and clinicians were unaware of the actual dose of warfarin that was administered. After the 5-day initiation period, dosage was adjusted during the first 4 weeks using standardized dose-adjustment techniques, starting with the doses predicted by the algorithms and making the same relative adjustments on the basis of the INR in the two study groups. Clinicians were informed of the relative dose change at each INR measurement but not the actual dose of warfarin. Subjects were to be followed for a total of 6 months. The primary outcome was the percentage of time that the subject's INR was in the therapeutic range (2 to 3) from the completion of the intervention period (day 4 or 5) through day 28 of therapy. Secondary outcomes included a composite outcome of any INR of 4 or more, major bleeding, or thromboembolism in the first 4 weeks. Conclusions: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

  Study phs004634

• The Genomic and Transcriptomic Landscape of a HeLa Cell Line

  HeLa is the most widely used model cell line for studying human cellular and molecular biology. To date, no genomic reference for this cell line has been released, and experiments have relied on the human reference genome. Effective design and interpretation of molecular genetic studies performed using HeLa cells require accurate genomic information. Here we present a detailed genomic and transcriptomic characterization of a HeLa cell line. We performed DNA and RNA sequencing of a HeLa Kyoto cell line and analyzed its mutational portfolio and gene expression profile. Segmentation of the genome according to copy number revealed a remarkably high level of aneuploidy and numerous large structural variants at unprecedented resolution. Some of the extensive genomic rearrangements are indicative of catastrophic chromosome shattering, known as chromothripsis. Our analysis of the HeLa gene expression profile revealed that several pathways, including cell cycle and DNA repair, exhibit significantly different expression patterns from those in normal human tissues. Our results provide the first detailed account of genomic variants in the HeLa genome, yielding insight into their impact on gene expression and cellular function as well as their origins. This study underscores the importance of accounting for the strikingly aberrant characteristics of HeLa cells when designing and interpreting experiments, and has implications for the use of HeLa as a model of human biology. Copyright Landry et al., "The Genomic and Transcriptomic Landscape of a HeLa Cell Line," G3: Genes | Genomes | Genetics (2013).

  Study phs000643

• The Study of Soy Isoflavones in Asthma (SOYA-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.ObjectivesTo determine whether participants with poorly controlled asthma have improved asthma control and lung capacity when prescribed a soy isoflavone supplement versus a placebo.BackgroundThe prevalence of asthma is determined by multiple environmental and genetic factors, and over the last several decades, both the prevalence and severity of asthma have increased. Specific causes remain unknown, but diet is one of the environmental factors associated with increased prevalence and severity.Previous studies had shown that those who consume soy isoflavones have better lung function compared to those who do not. The study focused on two particular iosflavones, genistein and daidzein, based on the strong preclinical and epidemiological data that supported the prediction of beneficial dietary effects for asthma patients. At the cellular level, genistein exerts antioxidant effects that are equal to or greater than those of vitamin C. Prior to the clinical trial, recent in vitro results showed that genistein inhibits synthesis of human peripheral blood eosinophil cysteinyl leukotrienes via inhibition of 5-lipoxygenase. Synthesis of the eosinophil cysteinyl leukotrienes is a key pathways that may contribute to asthma severity.ParticipantsEligible participants were over the age of 12, of either gender, and were non-smokers for 6 months or longer with a less than 10 pack-year smoking history. The SOYA trial had 193 participants randomized into the placebo and soy isoflavone arms for a total of 386 participants. 179 participants in the placebo arm and 166 participants in the soy isoflavone arm completed the trial, which was defined as having an FEV1 measurement at 24 weeks.Participants were included if they had been diagnosed by a physician with asthma, were currently prescribed daily controller asthma medication, or had a FEV1 equal or greater than 50% predicted pre-bronchodilator and/or at least 12% increase in FEV1 15-3 minutes after inhaling 2-4 puffs of albuterol or positive methacholine challenge (20% fall in FEV1 at less than 8 mg/mL) with either parameter available from the previous two years. Participants with poor asthma control were included if they met at least one of the following: a score of 1.5 or greater on the Juniper Asthma Control Questionnaire, use of beta-agonist for asthma symptoms two or more times per week, nocturnal awakening with asthma symptoms more than once per week, and/or two or more episodes of asthma symptoms in the past 12 months with each requiring at least one of the following: emergency department visit, unscheduled physician visit, prednisone course, and/or hospitalization.Participants were excluded from the trial for potential non-adherence or allergy to treatment, not meeting FEV inclusion criteria, use of concurrent and/or prior (DesignSOYA was a phase 4 interventional clinical trial. The study was multicenter, randomized, and double blind. Parallel assignment treatment arms were structured to determine the efficacy of soy supplementation and diet modification on asthma control.The primary outcome measured was the mean change in forced expiratory volume in the first second (FEV1), at the 24 week visit. Secondary outcomes were asthma symptoms, episodes of poor asthma control, Asthma Control Test score, and systemic and airway biomarkers of inflammation.Participants were randomly assigned in a 1:1 allocation ratio to receive either the soy isoflavone supplement or matching placebo twice daily for six months. Participants were instructed to keep daily diaries recording the following: morning peak expiratory flow, medication use, and asthma symptoms. Participants reported taking at least 1 dose of the study treatment on more than 90% of follow-up days. Clinical assessments and procedures were completed every 4 weeks for a total of 24 weeks. The Block Food Frequency Questionnaire and Soy Foods Screener were administered at visits 2 and 9. Data from daily diaries and pill counts were used to evaluate adherence to the treatment protocol. Each participant's overall diet and dietary soy intake were analyzed at baseline and at 24 weeks to assess stability of diet and nutrient intake during the study.ConclusionsParticipants who received the soy isoflavone supplement exhibited an increase in mean plasma genistein levels; however, no clinically significant improvement was observed in the primary end point of FEV1 at 24 weeks post-randomization between participants treated with soy isoflavone supplement and placebo.JAMA. 2015 May 26;313(20):2033-43

  Study phs004683

• Genetics of Antinuclear Antibodies

  Antinuclear antibodies (ANA) are antibodies that react against self-antigens in the cell. While it has been reported that 12 to 20% of the general population have a positive ANA test, the genetics of ANA positivity is unknown. We performed a genome wide-association study for positive ANA tests among individuals without an ANA related autoimmune disease in the Vanderbilt University Medical Center (VUMC) DNA biobank linked to the de-identified electronic health record (EHR) system. The study is funded by the National Institute of Arthritis and Musculoskeletal and Skin diseases (NIAMS) grant R01AR076516.

  Study phs003189

• Multiomic Landscape of Multiple Myeloma Precursor and Relapsed Disease

  Multiple myeloma (MM) is a treatable, though incurable, plasma cell malignancy. The molecular mechanisms driving disease onset and the emergence of drug resistance remain elusive. To better characterize the mutational, transcriptional, and epigenetic alterations that accompany MM disease evolution, we accessed molecular data from MM patients treated at Moffitt Cancer Center, with bone marrow biopsies collected between 2011 and 2023.We performed scMultiome (single-cell, paired RNA/ATAC-Seq, 10x Genomics) on 18 CD138+-selected bone marrow aspirate samples, including: 2 healthy donors, 3 patients with monoclonal gammopathy of undetermined significance (MGUS), 4 with smoldering myeloma (SMM), 3 with newly diagnosed MM (NDMM), 1 with early relapse MM (ERMM, 1 to 3 lines of therapy), and 5 with late relapse MM (LRMM, 4 or more lines of therapy). Our dataset includes a sequential sample: a patient with a premalignant condition ("scMultiome_SMM_4") that progressed to active myeloma ("scMultiome_NDMM_3"). These data allow for the assessment of transcriptional and epigenetic dysregulation at the cellular level. Our findings illustrate the dynamic epigenetic and transcriptional landscapes that accompany MM disease progression.We also conducted CUT&Tag analysis on 4 NDMM and 4 LRMM samples to map histone modifications, specifically H3K27ac, to investigate their role in transcriptional reprogramming observed in advanced stages of MM. This analysis revealed sample heterogeneity in terms of super-enhancer-regulated genes associated with active transcription.This cohort also includes samples from the clinical trial NCT04151667, “Daratumumab-Based Response-Adaptive Therapy for Older Adults With Newly Diagnosed Multiple Myeloma.” We performed scRNAseq (single-cell RNA sequencing, 10x Genomics) on 30 CD138+-selected bone marrow aspirate samples and 31 pre-sort samples featuring bone marrow mononuclear cells of various cell types from 5 healthy donors and 11 patients with newly diagnosed MM (NDMM). Our dataset includes sequential samples for all 11 NDMM patients, both prior to induction therapy (denoted by ‘a') with Daratumumab and Dexamethasone, and at cycle 2 day 22 (C2D22, i.e., 60 days after induction therapy start, denoted by ‘b'). For three NDMM patients, we also have samples at relapse (denoted by ‘c'). These data allow for the assessment of transcriptional dysregulation at the single-cell level in both the tumor and immune-tumor microenvironment, associated with Daratumumab treatment in NDMM patients.In addition to the molecular data, demographic, and phenotypic information for all samples is provided.

  Study phs003892

• Center for Common Disease Genomics (CCDG) - Neuropsychiatric: Introduction of Exome/Genome Sequencing

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs004430

• Genetics of IgA Vasculitis

  IgA vasculitis (IgAV), also known as Henoch-Schönlein purpura (HSP), is the most common form of childhood vasculitis with skin and systemic manifestations. It's characterized by IgA deposition in blood vessel walls in the skin, joints, gastrointestinal tract, and the glomerular mesangium. This dataset is from a genome-wide association study (GWAS) designed to identify novel genetic risk loci for IgAV. The participants of the GIGA-kids cohort were genotyped by Illumina Multi-Ethnic Global Array, consisting of 741 IgAV cases and 2,167 healthy controls of European ancestry. These cohorts were used in the GWAS meta-analysis, as described in the manuscript entitled "Genome-wide studies define new genetic mechanisms of IgA vasculitis" (Nature Communications 2026, under review).

  Study phs004179

• Genetics of Eating Disorders

  This genetic study examines Anorexia Nervosa, Bulimia Nervosa, and Binge Eating Disorder. We performed whole exome sequencing (WES) on 93 unrelated individuals with eating disorders (38 restricted-eating, 55 binge-eating) to identify novel damaging variants. Using an unbiased, data-driven approach, we prioritized candidate genes with an excessive burden of predicted damaging variants. We then empirically tested one top candidate pathway in a mouse model of binge-like eating. We identified an excess of novel damaging variants in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. The list of genes significantly enriched (OR = 4.6, p

  Study phs001414

• Genetic Analysis of Tuberous Sclerosis Complex (TSC) Hypomelanotic Macules

  In this study we searched for mutations in the TSC1 and TSC2 genes in cultured melanocytes from individuals with the genetic disease Tuberous Sclerosis Complex.

  Study phs001236

• Perinatal Elimination of Genetically Aberrant Neurons from Human Cerebral Cortex

  In this study, we used two independent single-cell whole-genome sequencing methods, Tn5-transposase-based amplification (TbA) and primary template amplification (PTA), to profile somatic copy number variants (CNVs) in single cortical neurons from postmortem human brain donors ranging from gestational week 14 to over 89 years of age, complemented by single-nucleus multiome (ATAC- and RNA-seq) profiling of a subset of the same donors. We found that widespread, multi-chromosomal CNVs were present in up to 46% of prenatal neurons, but this proportion dropped four- to five-fold after birth. Neurons with widespread CNVs were eliminated mostly around the time of birth, while neurons carrying smaller CNVs continued to be cleared more gradually throughout postnatal life. CNV breakpoints tracked closely with DNA replication timing, and recurrent copy losses were associated with double-strand break hotspots, implicating replication stress and NHEJ-mediated repair in dividing progenitor cells as sources of these lesions. Consistent with chromosome missegregation during development, we also observed micronuclei containing missegregated chromosomal material in the prenatal cortex, with micronuclear genomic content declining with age in parallel with the loss of CNV-bearing neurons. Neurons with a high CNV burden showed dysregulated synaptic gene expression and increased cell-death pathway activity, and the genomic regions spared from CNVs in surviving neurons were enriched for autism-risk and postsynaptic genes, evidence that this elimination is selective rather than random. Together, these findings suggest that clearance of genomically defective neurons, coupled to synapse formation, acts as a genome quality-control mechanism across brain development and aging. Through this accession, we are releasing single-cell and bulk whole-genome and multiome sequencing data for the postmortem brain donors and one iPSC-derived reference line.

  Study phs004946