3334 results for "*geneti*"

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• The Environmental Determinants of Diabetes in the Young Study (TEDDY)

  Study Overview The Environmental Determinants of Diabetes in the Young (TEDDY) Study is a longitudinal study that investigates genetic and genetic-environmental interactions, including gestational events, childhood infections, dietary exposures, and other environmental factors after birth, in relation to the development of islet autoimmunity and type 1 diabetes (T1D). A consortium of six clinical centers assembled to participate in the development and implementation of the study to identify environmental triggers for the development of islet autoimmunity and T1D in genetically susceptible individuals. Beginning in 2004, the TEDDY study screened over 400,000 newborns for high-risk HLA-DR, DQ genotypes from both the general population and families already affected by T1D. The TEDDY study enrolled around 8,676 participants across six clinical centers worldwide (Finland, Germany, Sweden and three in the United States) in the 15-year prospective follow-up. Participants are followed every three months for islet autoantibody (IA) measurements with blood sampling until four years of age and then at least every six months until the age of 15. After the age of four, autoantibody positive participants continue to be followed at three month intervals and autoantibody negative participants are followed at six-month intervals. In addition to the analysis of autoantibodies, additional data and sample collection are performed at each visit. Parents collect monthly stool samples in early childhood. The parents also fill out questionnaires at regular intervals in connection with study visits and record information about diet and health status in the child's TEDDY Book between visits. Continued long-term follow-up of the currently active TEDDY participants will provide important scientific information on early childhood diet, reported and measured infections, vaccinations, and psychosocial stressors that may contribute to the development of type 1 diabetes and islet autoimmunity. Additional information on the TEDDY study is available in the following articles: Rewers et al., 2008, PMID: 19120261 and Hagopian et al., 2006, PMID: 17130573. Details of the TEDDY protocol can be found in Hagopian et al., 2011, PMID: 21564455. TEDDY data currently available in dbGaP include: gene expression, SNPs, exome, microbiome (gut, nasal, and plasma), RNA sequencing, and whole genome sequencing. For more information on TEDDY Study version history please refer to TEDDY Study dbGaP README File. ImmunoChip SNP DNA from whole blood samples on study participants and their family members (mothers, fathers, and siblings) was obtained and used for SNP genotyping. Genotyping was performed by the Center for Public Health Genomics at the University of Virginia using the Illumina ImmunoChip SNP array, which contains around 196,000 SNPs from 186 regions associated with 12 autoimmune diseases (Hadley et al., 2015, PMID: 26010309). Data cleaning and validation included the removal of subjects with a low call rate (< 5% SNPs missing) and differences in reported sex and prior genotyping at the TEDDY HLA laboratory. Additionally, SNPs with a low call rate or Hardy-Weinberg equilibrium P value < 10-6, except for chromosome 6 due to HLA eligibility requirements, were removed from the final dataset (Törn et al., 2015, PMID: 25422107).TEDDY-T1DExome ArrayDNA from whole blood samples on study participants and their family members (mothers, fathers, and siblings) was obtained and used for genotyping. 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. Gene Expression The TEDDY study collected peripheral blood for the extraction of total RNA from enrolled children starting at 3 months of age, and then at 3 month intervals up to 48 months and then biannually. Total RNA was extracted using a high throughput (96-well format) extraction protocol using magnetic (MagMax) beads technology at the TEDDY RNA Laboratory, Jinfiniti Biosciences in Augusta, GA. Purified RNA (200 ng) was further used for cRNA amplification and labeling with biotin using Target Amp cDNA synthesis kit (Epicenter catalog no. TAB1R6924). Labeled cRNA was hybridized to the Illumina HumanHT-12 Expression BeadChips based on the manufacturer's instructions. The HumanHT-12 Expression BeadChip provides coverage for more than 47,000 transcripts and known splice variants across the human transcriptome. Microbiome The TEDDY microbiome study aimed to characterize the longitudinal development of the microbiome, including bacteria, viruses and other microorganisms in the gut, plasma, and nasal cavity of prediabetic and diabetic subjects compared to autoantibody negative non-diabetic subjects. Stool samples used were collected monthly from 3 to 48 months, after which stool samples were collected every 3 months. Nasal swab samples were collected every 3 months starting at 9 months of age until 48 months, after which nasal swabs were collected every 6 months. Plasma samples were collected every 3 months starting at 3 months of age until 48 months, after which plasma samples were collected every 6 months. If the subject was autoantibody positive at 48 months then they remained on the 3 month collection interval for nasal swab and plasma samples. Samples underwent 16s rRNA gene sequencing, DNA and viral RNA metagenomics shotgun sequencing, and sequencing of the internal transcribed spacer (ITS) regions. Additional information on the TEDDY microbiome data is available in the following articles: Vatanen et al., 2018, PMID: 30356183, Stewart et al., 2018, PMID: 30356187, and Vehik et al., 2020, PMID: 31792456. RNA Sequencing The TEDDY study aimed to characterize the transcriptome in subjects with islet autoimmunity and type 1 diabetes compared to matched control subjects. Peripheral blood was collected to extract total RNA from enrolled children starting at 3 months of age, and then at 3 month intervals up to 48 months and then biannually. Total RNA was extracted using a high throughput (96-well format) extraction protocol using magnetic (MagMax) beads technology at the TEDDY RNA Laboratory, Jinfiniti Biosciences in Augusta, GA. Purified RNA was then sent to the Broad Institute for the generation of the TEDDY RNA sequencing (RNA-Seq) data. The RNA samples were prepped using Superscript III reverse transcriptase and Illumina's TruSeq Stranded mRNA Sample Prep Kit. The TruSeq libraries were run on the Illumina HiSeq2500 platform. Whole Genome Sequencing The TEDDY study aimed to conduct deep whole genome sequencing and examine the genomic variations in subjects with islet autoimmunity and type 1 diabetes compared to matched autoantibody negative and non-diabetic children. DNA from whole blood was obtained from TEDDY children for whole genome sequencing. The WGS data were generated on the Illumina HiSeq X Ten system.

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• Genomic Variation in Diffuse Large B Cell Lymphomas

  Integrative analysis of genetic lesions in 574 diffuse large B cell lymphomas (DLBCL). The study investigates genomic structural variation, genetic alteration and its effect on the development and biology of lymphomas by using high throughput sequencing, gene expression, and methylation status.

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• Genomic Resistance Patterns to Second Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castrate-Resistant Prostate Cancer

  We examined genetic resistance to second generation androgen targeting therapies (abiraterone acetate or enzalutamide) by analyzing whole exome sequencing of patient-matched pre-treatment and post-resistance tumors from a series of castrate-resistant prostate cancer (CRPC) patients. Abiraterone resistant tumors harbored alterations in AR and MYC, whereas patients treated with enzalutamide had acquired alterations in the cell cycle pathway. We experimentally confirmed expression of cell-cycle kinases sufficed to drive enzalutamide resistance, which was mitigated through CDK4/6 blockade. These observations link genetic resistance to specific therapeutic agents to inform strategies in genomically selected advanced CRPC.

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• Multiregion Sequencing of Localized Prostate Cancer

  Ten patients with treatment-naïve, locally advanced or localized prostate cancer underwent radical prostatectomy. Pathological stage ranged from T2aN0 to T3bN1, and Gleason scores from 3+4 to 4+5. Tumor foci were mapped, and DNA was extracted from multiple (5-9) regions from a single, contiguous index focus. Whole exome sequencing was performed to identify single nucleotide variants and indels, and low coverage whole genome sequencing was performed to estimate copy number variation. Phylogenetic relationships between foci was determined, and alterations associated with advanced disease or response to targeted therapy were identified.

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• NHLBI TOPMed: Pharmacogenomics of Hydroxyurea in Sickle Cell Disease (PharmHU)

  Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin (HbS) within circulating erythrocytes resulting in hemolytic anemia, vascular occlusion, and end organ damage due to alterations in the shape and deformability of the cell membrane. The disease is inherited in an autosomal recessive pattern, and is most commonly caused by a single nucleotide substitution in the hemoglobin subunit beta (HBB) gene located on chromosome 11. Participants in this study include children with SCD treated with hydroxyurea to pharmacologically increase fetal hemoglobin (HbF) levels and reduce disease severity. Therefore, the primary phenotype of interest in this study is the change in HbF levels in response to hydroxyurea treatment. Genetic factors have been shown to influence inter-individual variation in drug response, and identification of novel genes and variants associated with clinical outcomes in SCD will be achieved through collaboration between Baylor College of Medicine, Augusta University, Columbia University Medical Center, Emory University School of Medicine and Children's Healthcare of Atlanta, and St. Jude Children's Research Hospital. The NHLBI TOPMed Program is designed to generate scientific resources to enhance understanding of fundamental biological processes that underlie heart, lung, blood and sleep disorders (HLBS). It is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment.

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• NHLBI TOPMed: Recipient Epidemiology and Donor Evaluation Study-III Brazil Sickle Cell Disease Cohort (REDS-BSCDC)

  Establishing a Brazilian Sickle Cell Disease Cohort and Identifying Molecular Determinants of Response to Transfusions, Genetic Determinants of Alloimmunization, and Risk Factors Associated with HIV Infection. The REDS-III Brazil SCD Cohort study focused on transfusion practices and predictors of health outcomes in patients with Sickle Cell Disease (SCD) and began in the Fall of 2013. The four primary aims of this study are: 1) Aim A - Establish a cohort of SCD patients with a comprehensive centralized electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; 2) Aim B - Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; 3) Aim C - Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA) study in transfused SCD patients; and, 4) Aim D - Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients. Patients are enrolled from six hospitals affiliated with the participating four REDS-III Brazil hemocenters.

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• NHLBI TOPMed: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE)

  ECLIPSE was a longitudinal observational study of 2164 COPD subjects and a smaller number of smoking controls (337) and nonsmoking controls (245) followed regularly for three years, with three chest CT scans (at baseline, one year, and three years) (Vestbo et al., 2008, PMID: 18216052). Subjects were enrolled at clinical centers in the US, Canada, Europe, and New Zealand. Inclusion criteria included subjects ages 40-75, at least 10 pack-years of smoking, and spirometry in GOLD grades 2-4 (COPD cases) or normal spirometry with post-bronchodilator FEV1 >85% (predicted) and FEV1/FVC>0.7 (controls). Study visits were performed at enrollment, three months, and every six months thereafter with spirometry, questionnaires, and other clinical evaluations. The ECLIPSE CT scans have been analyzed with the VIDA software for emphysema and airway phenotypes. ECLIPSE has provided key insights into the clinical epidemiology of COPD, including COPD exacerbations (Hurst, et. al., 2010, PMID: 20843247) and lung function decline in COPD (Vestbo, et. al., 2011, PMID: 21991892). ECLIPSE has been used in a number of genetic studies of COPD susceptibility and protein biomarkers (Faner, et. al., 2014, PMID: 24310110). Genome-wide gene expression microarray data are available in 147 induced sputum samples from COPD subjects and 248 peripheral blood samples from COPD and control subjects. Phenotype data for ECLIPSE subjects is available through dbGaP phs001252.

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• Clonal Evolution and Transcriptomic Analysis of Chronic Lymphocytic Leukemia Treated with Ibrutinib

  Disease progression has been increasingly appreciated with the use of ibrutinib to treat chronic lymphocytic leukemia (CLL). Understanding the pattern of clonal evolution and transcriptomic changes during the early treatment period with ibrutinib may provide insight into the mechanisms of resistance. We performed whole exome sequencing on sequential samples with matched germline controls from 61 patients with CLL during the first 12 months of ibrutinib monotherapy or ibrutinib in combination with rituximab. Additionally, RNA sequencing was done on a subset of 14 patients treated with ibrutinib monotherapy. The presence of clonal shifts was associated with an increased risk of disease progression, suggesting that resistant clones are more likely to emerge in CLL with greater evolutionary capacity.This cohort was later augmented with additional data (including data from 15 additional patients). In total, this second set of data contained whole exome sequencing (31 samples), RNA sequencing (6 samples) and reduced representation bisulfite sequencing (67 samples) for CLL samples and used them to identify expression subtypes of CLL. In an integrative analysis of genetic, transcriptomic, and epigenetic data, incorporating known and newly identified subtypes of CLL, we built new models to improve patient prognostication.

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• Field Studies of Human Immunity to Amebiasis in Bangladesh (NIH Birth Cohort) and Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh (PROVIDE)

  NIH birth cohort study Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission PROVIDE (Performance of Rotavirus and Oral Polio Vaccines in Developing Countries) Study Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Environmental enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. The primary objective of the study was to determine the association of environmental enteropathy with the efficacy of oral polio and rotavirus vaccines in children in Bangladesh. Secondary and exploratory objectives were designed to address other possible causes of oral vaccine underperformance including malnutrition, interference with maternal or breastmilk antibodies, changes in gut microbiota, and genetic susceptibility. The PROVIDE study was structured as a 2x2 clinical trial with a prospective birth cohort enrollment of 700 infants and their mothers in the urban slum of Mirpur, Dhaka, Bangladesh. All children received the full series of Bangladesh's Expanded Program on Immunization vaccines, including oral polio vaccine (OPV) and followed for their first 2 years of life. Half the children were randomized to receive an inactivated polio vaccine (IPV) for their 4th dose at 39 weeks instead of the standard OPV dose. In the other trial, half the infants received the 2-dose rotavirus vaccine (Rotarix) with delayed dosing at 10 and 17 weeks of age. A detailed description of the study design and procedures can be obtained from PROVIDE methods publication: Kirkpatrick B.D., Colgate R.E., Mychaleckyj J.C., Haque R., Dorothy D.M., Carmolli M.P., et al. (2015) Am J Trop Med Hyg 92, 744-751 The Poliovirus trial and results are described in Mychaleckyj et al, Vaccine 2016 The Rotavirus trial and results are described in Colgate et al, Clin Infect Dis 2016 The PROVIDE infants were genotyped on a custom Affymetrix Axiom array (30K SNPs) at the University of Virginia Center for Public Health Genomics; and on a pre-production version of the Illumina MEGA v2 chip at the Wellcome Trust Sanger Institute, UK. The latter genotyping was performed under the auspices of the VaccGene Consortium. Analyses are ongoing to identify variants associated with the included phenotypes. A manuscript describing the genotyping methods and analysis is in preparation for the initial phenotypes. The Infection Malnutrition Bangladesh Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001475 Infection Malnutrition Bangladesh Cohort. phs001476 Amebiasis Immunity phs001478 Polio Rotavirus Vaccines phs001665 Cryptosporidiosis Enteropathogens

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• Genetics of Chemotherapy Induced Peripheral Neuropathy in N08C1 and N08CB

  Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting toxicity of chemotherapy treatment. CIPN severity varies widely between cancer patients, and previous studies had found evidence of genes and single nucleotide variants (SNV) being associated with CIPN. The goal of this study was to further identify genetic markers and pathways associated with CIPN severity using whole exome sequencing (WES) and whole genome sequencing (WGS) of participants in two clinical studies which collected longitudinal patient-reported outcome (PRO) measures of CIPN. NCCTG/Alliance study N08C1 was a prospective cohort study of the natural history of paclitaxel-associated acute pain syndrome (P-APS) and CIPN. NCCTG/Alliance trial N08CB was a randomized, placebo-controlled trial of calcium and magnesium for prevention of oxaliplatin-induced sensory neuropathy in which the treatment had no significant effect on either acute pain or sensory neuropathy. Both N08C1 and N08CB collected patient assessments of CIPN symptoms before each cycle of chemotherapy using the EORTC QLQ-CIPN20 instrument. For this study, CIPN cases were selected from each of N08C1 and N08CB as those patients with the most severe CIPN symptoms (assessed longitudinally). CIPN controls were selected as those with the least severe symptoms. WGS was obtained for N08C1 samples (WES had been obtained and analyzed previously), and WES was obtained for N08CB samples.

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