Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
N Engl J Med ; 381(7): 668-676, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412182

RESUMO

Knowledge gained from observational cohort studies has dramatically advanced the prevention and treatment of diseases. Many of these cohorts, however, are small, lack diversity, or do not provide comprehensive phenotype data. The All of Us Research Program plans to enroll a diverse group of at least 1 million persons in the United States in order to accelerate biomedical research and improve health. The program aims to make the research results accessible to participants, and it is developing new approaches to generate, access, and make data broadly available to approved researchers. All of Us opened for enrollment in May 2018 and currently enrolls participants 18 years of age or older from a network of more than 340 recruitment sites. Elements of the program protocol include health questionnaires, electronic health records (EHRs), physical measurements, the use of digital health technology, and the collection and analysis of biospecimens. As of July 2019, more than 175,000 participants had contributed biospecimens. More than 80% of these participants are from groups that have been historically underrepresented in biomedical research. EHR data on more than 112,000 participants from 34 sites have been collected. The All of Us data repository should permit researchers to take into account individual differences in lifestyle, socioeconomic factors, environment, and biologic characteristics in order to advance precision diagnosis, prevention, and treatment.


Assuntos
Bancos de Espécimes Biológicos , Pesquisa Biomédica , Estudos de Coortes , Conjuntos de Dados como Assunto , Registros Eletrônicos de Saúde , Inquéritos Epidemiológicos , Humanos , Estudos Observacionais como Assunto , Medicina de Precisão , Projetos de Pesquisa , Estados Unidos
2.
Epidemiology ; 30(4): 597-608, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31045611

RESUMO

BACKGROUND: The All of Us Research Program is building a national longitudinal cohort and collecting data from multiple information sources (e.g., biospecimens, electronic health records, and mobile/wearable technologies) to advance precision medicine. Participant-provided information, collected via surveys, will complement and augment these information sources. We report the process used to develop and refine the initial three surveys for this program. METHODS: The All of Us survey development process included: (1) prioritization of domains for scientific needs, (2) examination of existing validated instruments, (3) content creation, (4) evaluation and refinement via cognitive interviews and online testing, (5) content review by key stakeholders, and (6) launch in the All of Us electronic participant portal. All content was translated into Spanish. RESULTS: We conducted cognitive interviews in English and Spanish with 169 participants, and 573 individuals completed online testing. Feedback led to over 40 item content changes. Lessons learned included: (1) validated survey instruments performed well in diverse populations reflective of All of Us; (2) parallel evaluation of multiple languages can ensure optimal survey deployment; (3) recruitment challenges in diverse populations required multiple strategies; and (4) key stakeholders improved integration of surveys into larger Program context. CONCLUSIONS: This efficient, iterative process led to successful testing, refinement, and launch of three All of Us surveys. Reuse of All of Us surveys, available at http://researchallofus.org, may facilitate large consortia targeting diverse populations in English and Spanish to capture participant-provided information to supplement other data, such as genetic, physical measurements, or data from electronic health records.

5.
Neuroepigenetics ; 1: 2-13, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25722961

RESUMO

Long-lived post-mitotic cells, such as the majority of human neurons, must respond effectively to ongoing changes in neuronal stimulation or microenvironmental cues through transcriptional and epigenomic regulation of gene expression. The role of epigenomic regulation in neuronal function is of fundamental interest to the neuroscience community, as these types of studies have transformed our understanding of gene regulation in post-mitotic cells. This perspective article highlights many of the resources available to researchers interested in neuroepigenomic investigations and discusses some of the current obstacles and opportunities in neuroepigenomics.

6.
Methods Mol Biol ; 1238: 27-49, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25421653

RESUMO

This chapter describes resources and technologies generated by the NIH Roadmap Epigenomics Program that may be useful to epigenomics researchers investigating a variety of diseases including cancer. Highlights include reference epigenome maps for a wide variety of human cells and tissues, the development of new technologies for epigenetic assays and imaging, the identification of novel epigenetic modifications, and an improved understanding of the role of epigenetic processes in a diversity of human diseases. We also discuss future needs in this area including exploration of epigenomic variation between individuals, single-cell epigenomics, environmental epigenomics, exploration of the use of surrogate tissues, and improved technologies for epigenome manipulation.


Assuntos
Epigenômica/métodos , Técnicas Genéticas , National Institutes of Health (U.S.) , Animais , Recursos em Saúde , Humanos , Características de Residência , Estados Unidos
9.
PLoS One ; 4(4): e5225, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19381300

RESUMO

Commercial SNP microarrays now provide comprehensive and affordable coverage of the human genome. However, some diseases have biologically relevant genomic regions that may require additional coverage. Addiction, for example, is thought to be influenced by complex interactions among many relevant genes and pathways. We have assembled a list of 486 biologically relevant genes nominated by a panel of experts on addiction. We then added 424 genes that showed evidence of association with addiction phenotypes through mouse QTL mappings and gene co-expression analysis. We demonstrate that there are a substantial number of SNPs in these genes that are not well represented by commercial SNP platforms. We address this problem by introducing a publicly available SNP database for addiction. The database is annotated using numeric prioritization scores indicating the extent of biological relevance. The scores incorporate a number of factors such as SNP/gene functional properties (including synonymy and promoter regions), data from mouse systems genetics and measures of human/mouse evolutionary conservation. We then used HapMap genotyping data to determine if a SNP is tagged by a commercial microarray through linkage disequilibrium. This combination of biological prioritization scores and LD tagging annotation will enable addiction researchers to supplement commercial SNP microarrays to ensure comprehensive coverage of biologically relevant regions.


Assuntos
Comportamento Aditivo/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Animais , Humanos , Camundongos , Locos de Características Quantitativas
10.
Radiat Res ; 171(1): 77-88, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19138047

RESUMO

Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-1962). Cases with thyroid nodules (n = 907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, P = 0.03) and GFRA1 -193C>G (rs not assigned, P = 0.05) and decreased risk with XRCC1 R194W (rs1799782, P trend = 0.03) and TGFB1 T263I (rs1800472, P = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n = 25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% CI 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT P value = 0.02). Polymorphisms in RET signaling, DNA repair and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways such as genes in double-strand break repair, apoptosis and genes related to proliferation should also be pursued.


Assuntos
Reparo do DNA/efeitos da radiação , Exposição Ambiental/efeitos adversos , Neoplasias Induzidas por Radiação/genética , Armas Nucleares , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas c-ret/genética , Nódulo da Glândula Tireoide/genética , Adulto , Idoso , DNA/genética , Feminino , Predisposição Genética para Doença , Humanos , Cazaquistão , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Tireotropina/genética
11.
J Biomed Inform ; 41(5): 752-65, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18395495

RESUMO

OBJECTIVES: This paper illustrates how Semantic Web technologies (especially RDF, OWL, and SPARQL) can support information integration and make it easy to create semantic mashups (semantically integrated resources). In the context of understanding the genetic basis of nicotine dependence, we integrate gene and pathway information and show how three complex biological queries can be answered by the integrated knowledge base. METHODS: We use an ontology-driven approach to integrate two gene resources (Entrez Gene and HomoloGene) and three pathway resources (KEGG, Reactome and BioCyc), for five organisms, including humans. We created the Entrez Knowledge Model (EKoM), an information model in OWL for the gene resources, and integrated it with the extant BioPAX ontology designed for pathway resources. The integrated schema is populated with data from the pathway resources, publicly available in BioPAX-compatible format, and gene resources for which a population procedure was created. The SPARQL query language is used to formulate queries over the integrated knowledge base to answer the three biological queries. RESULTS: Simple SPARQL queries could easily identify hub genes, i.e., those genes whose gene products participate in many pathways or interact with many other gene products. The identification of the genes expressed in the brain turned out to be more difficult, due to the lack of a common identification scheme for proteins. CONCLUSION: Semantic Web technologies provide a valid framework for information integration in the life sciences. Ontology-driven integration represents a flexible, sustainable and extensible solution to the integration of large volumes of information. Additional resources, which enable the creation of mappings between information sources, are required to compensate for heterogeneity across namespaces. RESOURCE PAGE: http://knoesis.wright.edu/research/lifesci/integration/structured_data/JBI-2008/


Assuntos
Disciplinas das Ciências Biológicas/métodos , Sistemas de Gerenciamento de Base de Dados , Armazenamento e Recuperação da Informação/métodos , Integração de Sistemas , Tabagismo/genética , Tabagismo/metabolismo , Animais , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Redes Reguladoras de Genes , Humanos , Internet/organização & administração , Bases de Conhecimento , Redes Neurais (Computação) , Mapeamento de Interação de Proteínas/métodos , Semântica , Vocabulário Controlado
12.
Eur J Med Genet ; 51(2): 141-7, 2008 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18158280

RESUMO

To evaluate the potential contribution of mutations in the BRCA1 and BRCA2 genes to male breast cancer (MBC), we expanded a previous study to screen a total of 261 Israeli men diagnosed with breast carcinoma. A total of 21 BRCA2 6174delT and 8 BRCA1 185delAG mutations were found. Similar frequencies of BRCA1 and BRCA2 mutation carriers were found among Ashkenazi (12.8%) and non-Ashkenazi Jews (9.1%). The combined prevalence of BRCA1/BRCA2 founder mutations among Ashkenazi Jewish men is slightly higher than for women, due to a higher frequency of BRCA2 mutations.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Judeus/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose , Neoplasias da Mama Masculina/patologia , Efeito Fundador , Predisposição Genética para Doença , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco
15.
Mutat Res ; 602(1-2): 43-53, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17045619

RESUMO

The high mobility group A2 protein (HMGA2) has been implicated in the pathogenesis of mesenchymal tumors such as leiomyoma, lipoma and hamartoma. HMGA2 was pinpointed by mapping the breakpoints in the chromosomal translocations in 12q15, especially the t(12;14) that is commonly seen in uterine leiomyoma. It is generally assumed that altered expression of HMGA2 is an early event in the pathway to tumor formation. Here, we show evidence that three novel transcripts, A15, B6 and D12 are located within the HMGA2 gene itself and are transcribed from the opposite strand. These embedded transcripts are expressed at 6-20-fold higher levels in tumors compared to matched myometrium from the same patients. We estimate that the domain of increased expression extends 500kb on chromosome 12q15, and encompasses the majority of t(12;14) translocation breakpoints. However, a corresponding domain of consistently altered expression is not seen on chromosome 14 or outside of the chromosome 12 multiple aberration region. These data suggest that t(12;14) breakpoints contribute to the pathogenesis of uterine leiomyoma by interrupting a complex regulation of HMGA2 and other genes embedded within and around it. We also discovered a novel laminin receptor gene, transcribed from the opposite strand, within the promoter region of HMGA2. Although the roles for these embedded transcripts are still unknown, preliminary data suggest that they are members of the family of non-coding RNA and that they may play an important role in the pathology of uterine leiomyoma.


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 14 , Proteína HMGA2/genética , Leiomioma/genética , Translocação Genética , Neoplasias Uterinas/genética , Processamento Alternativo , Sequência de Aminoácidos , Sequência de Bases , Etiquetas de Sequências Expressas , Feminino , Proteína HMGA2/metabolismo , Humanos , Leiomioma/metabolismo , Leiomioma/patologia , Modelos Genéticos , Dados de Sequência Molecular , Miométrio/metabolismo , Regiões Promotoras Genéticas , Receptores de Laminina/genética , Neoplasias Uterinas/metabolismo
16.
Am J Epidemiol ; 164(8): 794-804, 2006 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16923772

RESUMO

Single nucleotide polymorphisms (SNPs) are the most common form of human genetic variation, with millions present in the human genome. Because only 1% might be expected to confer more than modest individual effects in association studies, the selection of predictive candidate variants for complex disease analyses is formidable. Technologic advances in SNP discovery and the ever-changing annotation of the genome have led to massive informational resources that can be difficult to master across disciplines. A simplified guide is needed. Although methods for evaluating nonsynonymous coding SNPs are known, several other publicly available computational tools can be utilized to assess polymorphic variants in noncoding regions. As an example, the authors applied multiple methods to select SNPs in DNA double-strand break repair genes. They chose to evaluate SNPs that occurred among a preexisting set of 57 validated assays and to justify new assay development for 83 potential SNPs in the DNA-dependent protein kinase catalytic subunit. Of the 140 SNPs, the authors eliminated 119 variants with low or neutral predictions. The existing computational methods they used and the semiquantitative relative ranking strategy they developed can be adapted to a priori SNP selection or post hoc evaluation of variants identified in whole genome scans or within haplotype blocks associated with disease. The authors show a "real world" application of some existing bioinformatics tools for use in large epidemiologic studies and genetic analyses. They also reviewed alternative approaches that provide related information.


Assuntos
Métodos Epidemiológicos , Predisposição Genética para Doença , Internet , Polimorfismo de Nucleotídeo Único , Algoritmos , Sequência de Aminoácidos , Sequência de Bases , Humanos
17.
AAPS J ; 8(1): E174-84, 2006 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-16584126

RESUMO

Pharmacogenetics/pharmacogenomics is the study of how genetic variation affects pharmacology, the use of drugs to treat disease. When drug responses are predicted in advance, it is easier to tailor medications to different diseases and individuals. Pharmacogenetics provides the tools required to identify genetic predictors of probable drug response, drug efficacy, and drug-induced adverse events-identifications that would ideally precede treatment decisions. Drug abuse and addiction genetic data have advanced the field of pharmacogenetics in general. Although major findings have emerged, pharmacotherapy remains hindered by issues such as adverse events, time lag to drug efficacy, and heterogeneity of the disorders being treated. The sequencing of the human genome and high-throughput technologies are enabling pharmacogenetics to have greater influence on treatment approaches. This review highlights key studies and identifies important genes in drug abuse pharmacogenetics that provide a basis for better diagnosis and treatment of drug abuse disorders.


Assuntos
Farmacogenética/métodos , Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias/genética , Variação Genética/genética , Humanos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia
18.
Cancer ; 101(12): 2809-16, 2004 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-15529312

RESUMO

BACKGROUND: Data addressing the interfamilial heterogeneity of melanoma are limited. In the current study, the authors assessed melanoma risk according to family history of melanoma and other melanoma-associated malignancies and evaluated the familial heterogeneity of melanomas, pancreatic malignancies, and gastrointestinal malignancies. METHODS: The authors obtained patient histories of malignancy in first-degree relatives as part of a clinic-based case-control study. The case group included 737 newly diagnosed patients with invasive melanoma, and the control group included 1021 outpatients from clinics at the same medical centers. To assess heterogeneity of risk among families affected by melanoma, a nonparametric method was used to detect extrabinomial variation. In addition, selected patients with melanoma (n=133) were tested for germline mutations in CDKN2A. RESULTS: The adjusted odds ratio associated with a family history of melanoma was 1.7 (95% confidence interval, 1.1-2.7). Family histories of pancreatic, gastrointestinal, brain, breast, or lymphoproliferative disease did not increase the risk of melanoma significantly. Among case families, significant evidence of familial heterogeneity was found for melanomas, but not for pancreatic or gastrointestinal malignancies. Two mutations in CDKN2A previously associated with melanoma risk were identified among the 133 patients tested in the case group; mutation detection did not differ between families with low and high heterogeneity scores. CONCLUSIONS: Familial heterogeneity testing in the study population did not improve the selection of high-risk families for genetic study. Even in a large case-control study, few families that had multiple members with melanoma were identified, and family members with pancreatic malignancies were rare.


Assuntos
Neoplasias Gastrointestinais/genética , Melanoma/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Estudos de Casos e Controles , Saúde da Família , Feminino , Genes p16 , Heterogeneidade Genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
20.
BMC Cancer ; 4: 9, 2004 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-15113441

RESUMO

BACKGROUND: Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFss1, IGFBP3) were evaluated. METHODS: Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported. RESULTS: Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3-3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1-3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6-29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFss1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P. CONCLUSION: Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted.


Assuntos
Neoplasias da Mama/genética , Reparo do DNA , Genes BRCA1 , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Estudos de Coortes , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA