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1.
Pharmacogenomics ; 20(15): 1103-1112, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31588877

RESUMO

Pharmacogenetic testing can help identify primary care patients at increased risk for medication toxicity, poor response or treatment failure and inform drug therapy. While testing availability is increasing, providers are unprepared to routinely use pharmacogenetic testing for clinical decision-making. Practice-based resources are needed to overcome implementation barriers for pharmacogenetic testing in primary care.The NHGRI's IGNITE I Network (Implementing GeNomics In pracTicE; www.ignite-genomics.org) explored practice models, challenges and implementation barriers for clinical pharmacogenomics. Based on these experiences, we present a stepwise approach pharmacogenetic testing in primary care: patient identification; pharmacogenetic test ordering; interpretation and application of test results, and patient education. We present clinical factors to consider, test-ordering processes and resources, and provide guidance to apply test results and counsel patients. Practice-based resources such as this stepwise approach to clinical decision-making are important resources to equip primary care providers to use pharmacogenetic testing.

2.
Cell ; 177(1): 58-69, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901549

RESUMO

Personalized medicine has largely been enabled by the integration of genomic and other data with electronic health records (EHRs) in the United States and elsewhere. Increased EHR adoption across various clinical settings and the establishment of EHR-linked population-based biobanks provide unprecedented opportunities for the types of translational and implementation research that drive personalized medicine. We review advances in the digitization of health information and the proliferation of genomic research in health systems and provide insights into emerging paths for the widespread implementation of personalized medicine.

3.
PLoS One ; 13(7): e0200486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044860

RESUMO

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

4.
N Engl J Med ; 378(12): 1096-1106, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29562163

RESUMO

BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS: A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS: A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).


Assuntos
17-Hidroxiesteroide Desidrogenases/genética , Fígado Gorduroso/genética , Predisposição Genética para Doença , Hepatopatias/genética , Mutação com Perda de Função , 17-Hidroxiesteroide Desidrogenases/metabolismo , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Doença Crônica , Progressão da Doença , Feminino , Variação Genética , Genótipo , Humanos , Modelos Lineares , Fígado/patologia , Hepatopatias/patologia , Masculino , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
5.
Genet Med ; 20(5): 554-558, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29261187

RESUMO

PurposeThe clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility.MethodsWhole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient-participants and their clinicians. We queried patient-participants' electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient-participants of eligible age who had begun risk management.ResultsThirty-seven MyCode patient-participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer-including a stage 1C fallopian tube cancer-via these procedures.ConclusionScreening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.


Assuntos
Bancos de Espécimes Biológicos , Detecção Precoce de Câncer/métodos , Genes BRCA1 , Genes BRCA2 , Mutação , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Pessoa de Meia-Idade , Linhagem , Sequenciamento Completo do Genoma
6.
JAMA Netw Open ; 1(5): e182140, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30646163

RESUMO

Importance: Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals. Objectives: To identify pathogenic and likely pathogenic (P/LP) BRCA1/2 variants in an unselected research cohort, and to characterize the features associated with P/LP variants. Design, Setting, and Participants: This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (Geisinger Health System, Danville, Pennsylvania) from January 1, 2014, to March 1, 2016. Participants are part of the DiscovEHR cohort and were identified through the Geisinger MyCode Community Health Initiative. They consented to a research protocol that included sequencing and return of actionable test results. Clinical data from electronic health records and clinical visits were correlated with variants. Comparisons were made between those with (cases) and those without (controls) P/LP variants in BRCA1/2. Main Outcomes: Prevalence of P/LP BRCA1/2 variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among BRCA1/2 variant carriers and noncarriers. Results: Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic BRCA1/2 variants and 267 (0.5%) were BRCA1/2 carriers. Of the 267 cases (148 [55.4%] were women and 119 [44.6%] were men with a mean [range] age of 58.9 [23-90] years), 183 (68.5%) received clinically confirmed results in their electronic health record. Among the 267 participants with P/LP BRCA1/2 variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had BRCA1 variants, and 172 (64.4%) had BRCA2 variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased BRCA1/2 carriers and in 56 (20.9%) of all 267 BRCA1/2 carriers. Among women, 31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers (odds ratio [OR], 5.95; 95% CI, 3.88-9.13; P < .001). Ovarian cancer history was present in 15 (10.1%) of 148 variant carriers and in 195 (0.6%) of 29 880 variant noncarriers (OR, 18.30; 95% CI, 10.48-31.4; P < .001). Among 89 BRCA1/2 carriers without prior testing but with comprehensive personal and family history data, 44 (49.4%) did not meet published guidelines for clinical testing. Conclusions and Relevance: This study found that compared with previous clinical care, exome sequencing-based screening identified 5 times as many individuals with P/LP BRCA1/2 variants. These findings suggest that genomic screening may identify BRCA1/2-associated cancer risk that might otherwise remain undetected within health care systems and may provide opportunities to reduce morbidity and mortality in patients.


Assuntos
Proteína BRCA1/análise , Proteína BRCA2/análise , Sequenciamento Completo do Exoma/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Bancos de Espécimes Biológicos/estatística & dados numéricos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Estudos Transversais , Detecção Precoce de Câncer/métodos , Exoma/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pennsylvania , Virulência/genética , Sequenciamento Completo do Exoma/estatística & dados numéricos
7.
Elife ; 62017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28895531

RESUMO

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.


Assuntos
Doenças do Colágeno/epidemiologia , Doenças do Colágeno/genética , Colágenos Fibrilares/genética , Epidemiologia Molecular , Linhagem , Adolescente , Adulto , Idoso , Criança , Feminino , Genótipo , Heterozigoto , Hispano-Americanos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Doenças Musculoesqueléticas/epidemiologia , Doenças Musculoesqueléticas/genética , Cidade de Nova Iorque/epidemiologia , Cidade de Nova Iorque/etnologia , Sequenciamento Completo do Genoma , Adulto Jovem
8.
Pharmacogenomics ; 18(10): 1013-1025, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28639489

RESUMO

Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.


Assuntos
Sistemas de Apoio a Decisões Clínicas/organização & administração , Registros Eletrônicos de Saúde/organização & administração , Pessoal de Saúde/educação , Farmacogenética/educação , Medicina de Precisão/métodos , Sistemas de Apoio a Decisões Clínicas/normas , Registros Eletrônicos de Saúde/normas , Medicina de Precisão/normas , Estados Unidos
9.
Science ; 354(6319)2016 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-28008010

RESUMO

Familial hypercholesterolemia (FH) remains underdiagnosed despite widespread cholesterol screening. Exome sequencing and electronic health record (EHR) data of 50,726 individuals were used to assess the prevalence and clinical impact of FH-associated genomic variants in the Geisinger Health System. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variant carriers had significantly increased risk of coronary artery disease. Only 24% of carriers met EHR-based presequencing criteria for probable or definite FH diagnosis. Active statin use was identified in 58% of carriers; 46% of statin-treated carriers had a low-density lipoprotein cholesterol level below 100 mg/dl. Thus, we find that genomic screening can prompt the diagnosis of FH patients, most of whom are receiving inadequate lipid-lowering therapy.


Assuntos
Corantes/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , Testes Genéticos , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Doença da Artéria Coronariana/epidemiologia , Assistência à Saúde , Registros Eletrônicos de Saúde , Exoma/genética , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Lipoproteínas LDL/sangue , Prevalência , Estados Unidos/epidemiologia
10.
Science ; 354(6319)2016 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-28008009

RESUMO

The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.


Assuntos
Prestação Integrada de Cuidados de Saúde , Doença/genética , Registros Eletrônicos de Saúde , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Desenho de Drogas , Frequência do Gene , Genômica , Humanos , Hipolipemiantes/farmacologia , Mutação INDEL , Lipídeos/sangue , Terapia de Alvo Molecular , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
11.
Per Med ; 13(2): 129-141, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27528879

RESUMO

AIM: The objective of this research was to assess medical student preparedness for the use of personalized medicine. MATERIALS & METHODS: A survey instrument measuring attitude toward personalized medicine, perceived knowledge of genomic testing concepts and perceived ability to apply genomics to clinical care was distributed to students in medical school (MS) years 1-4. RESULTS: Of 212 participants, 79% felt that it was important to learn about personalized medicine, but only 6% thought that their medical education had adequately prepared them to practice personalized medicine. Attitude did not vary across years; knowledge and ability increased after MS1, but not after MS2. CONCLUSION: While medical students support the use of personalized medicine, they do not feel prepared to apply genomics to clinical care.

12.
JAMA ; 315(1): 47-57, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26746457

RESUMO

IMPORTANCE: Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants. OBJECTIVE: To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014. EXPOSURES: One or more variants designated as pathogenic in SCN5A or KCNH2. MAIN OUTCOMES AND MEASURES: Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review. RESULTS: Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds. CONCLUSIONS AND RELEVANCE: Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.


Assuntos
Arritmias Cardíacas/genética , Registros Eletrônicos de Saúde , Canais de Potássio Éter-A-Go-Go/genética , Variação Genética , Laboratórios/normas , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Fenótipo , Idoso , Idoso de 80 Anos ou mais , Alelos , Arritmias Cardíacas/etnologia , Arritmias Cardíacas/fisiopatologia , Síndrome de Brugada/genética , Canal de Potássio ERG1 , Feminino , Predisposição Genética para Doença , Testes Genéticos/normas , Genômica , Heterozigoto , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estudos Prospectivos , Distribuição Aleatória , Estatísticas não Paramétricas , Adulto Jovem
13.
Pharmgenomics Pers Med ; 7: 227-40, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25206309

RESUMO

Clinical genetic testing began over 30 years ago with the availability of mutation detection for sickle cell disease diagnosis. Since then, the field has dramatically transformed to include gene sequencing, high-throughput targeted genotyping, prenatal mutation detection, preimplantation genetic diagnosis, population-based carrier screening, and now genome-wide analyses using microarrays and next-generation sequencing. Despite these significant advances in molecular technologies and testing capabilities, clinical genetics laboratories historically have been centered on mutation detection for Mendelian disorders. However, the ongoing identification of deoxyribonucleic acid (DNA) sequence variants associated with common diseases prompted the availability of testing for personal disease risk estimation, and created commercial opportunities for direct-to-consumer genetic testing companies that assay these variants. This germline genetic risk, in conjunction with other clinical, family, and demographic variables, are the key components of the personalized medicine paradigm, which aims to apply personal genomic and other relevant data into a patient's clinical assessment to more precisely guide medical management. However, genetic testing for disease risk estimation is an ongoing topic of debate, largely due to inconsistencies in the results, concerns over clinical validity and utility, and the variable mode of delivery when returning genetic results to patients in the absence of traditional counseling. A related class of genetic testing with analogous issues of clinical utility and acceptance is pharmacogenetic testing, which interrogates sequence variants implicated in interindividual drug response variability. Although clinical pharmacogenetic testing has not previously been widely adopted, advances in rapid turnaround time genetic testing technology and the recent implementation of preemptive genotyping programs at selected medical centers suggest that personalized medicine through pharmacogenetics is now a reality. This review aims to summarize the current state of implementing genetic testing for personalized medicine, with an emphasis on clinical pharmacogenetic testing.

14.
J Pers Med ; 4(1): 35-49, 2014 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25562141

RESUMO

This study assessed physician attitudes toward adopting genome-guided prescribing through clinical decision support (CDS), prior to enlisting in the Clinical Implementation of Personalized Medicine through Electronic Health Records and Genomics pilot pharmacogenomics project (CLIPMERGE PGx). We developed a survey instrument that includes the Evidence Based Practice Attitude Scale, adapted to measure attitudes toward adopting genome-informed interventions (EBPAS-GII). The survey also includes items to measure physicians' characteristics (awareness, experience, and perceived usefulness), attitudes about personal genome testing (PGT) services, and comfort using technology. We surveyed 101 General Internal Medicine physicians from the Icahn School of Medicine at Mount Sinai (ISMMS). The majority were residency program trainees (~88%). Prior to enlisting into CLIPMERGE PGx, most physicians were aware of and had used decision support aids. Few physicians, however, were aware of and had used genome-guided prescribing. The majority of physicians viewed decision support aids and genotype data as being useful for making prescribing decisions. Most physicians had not heard of, but were willing to use, PGT services and felt comfortable interpreting PGT results. Most physicians were comfortable with technology. Physicians who perceived genotype data to be useful in making prescribing decisions, had more positive attitudes toward adopting genome-guided prescribing through CDS. Our findings suggest that internal medicine physicians have a deficit in their familiarity and comfort interpreting and using genomic information. This has reinforced the importance of gathering feedback and guidance from our enrolled physicians when designing genome-guided CDS and the importance of prioritizing genomic medicine education at our institutions.

15.
PLoS One ; 6(10): e25535, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22043286

RESUMO

Opiates produce significant and persistent changes in synaptic transmission; knowledge of the proteins involved in these changes may help to understand the molecular mechanisms underlying opiate dependence. Using an integrated quantitative proteomics and systems biology approach, we explored changes in the presynaptic protein profile following a paradigm of chronic morphine administration that leads to the development of dependence. For this, we isolated presynaptic fractions from the striata of rats treated with saline or escalating doses of morphine, and analyzed the proteins in these fractions using differential isotopic labeling. We identified 30 proteins that were significantly altered by morphine and integrated them into a protein-protein interaction (PPI) network representing potential morphine-regulated protein complexes. Graph theory-based analysis of this network revealed clusters of densely connected and functionally related morphine-regulated clusters of proteins. One of the clusters contained molecular chaperones thought to be involved in regulation of neurotransmission. Within this cluster, cysteine-string protein (CSP) and the heat shock protein Hsc70 were downregulated by morphine. Interestingly, Hsp90, a heat shock protein that normally interacts with CSP and Hsc70, was upregulated by morphine. Moreover, treatment with the selective Hsp90 inhibitor, geldanamycin, decreased the somatic signs of naloxone-precipitated morphine withdrawal, suggesting that Hsp90 upregulation at the presynapse plays a role in the expression of morphine dependence. Thus, integration of proteomics, network analysis, and behavioral studies has provided a greater understanding of morphine-induced alterations in synaptic composition, and identified a potential novel therapeutic target for opiate dependence.


Assuntos
Morfina/farmacologia , Terminações Pré-Sinápticas/química , Proteômica , Transdução de Sinais/efeitos dos fármacos , Animais , Doença Crônica , Análise por Conglomerados , Proteínas de Choque Térmico HSP40 , Proteínas de Choque Térmico HSP70 , Proteínas de Choque Térmico HSP90 , Proteínas de Membrana , Chaperonas Moleculares , Morfina/administração & dosagem , Dependência de Morfina/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteínas/análise , Proteômica/métodos , Ratos , Transmissão Sináptica/efeitos dos fármacos
16.
Proteomics ; 9(12): 3303-15, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19562802

RESUMO

The application of proteomic techniques to neuroscientific research provides an opportunity for a greater understanding of nervous system structure and function. As increasing amounts of neuroproteomic data become available, it is necessary to formulate methods to integrate these data in a meaningful way to obtain a more comprehensive picture of neuronal subcompartments. Furthermore, computational methods can be used to make biologically relevant predictions from large proteomic data sets. Here, we applied an integrated proteomics and systems biology approach to characterize the presynaptic (PRE) nerve terminal. For this, we carried out proteomic analyses of presynaptically enriched fractions, and generated a PRE literature-based protein-protein interaction network. We combined these with other proteomic analyses to generate a core list of 117 PRE proteins, and used graph theory-inspired algorithms to predict 92 additional components and a PRE complex containing 17 proteins. Some of these predictions were validated experimentally, indicating that the computational analyses can identify novel proteins and complexes in a subcellular compartment. We conclude that the combination of techniques (proteomics, data integration, and computational analyses) used in this study are useful in obtaining a comprehensive understanding of functional components, especially low-abundance entities and/or interactions in the PRE nerve terminal.


Assuntos
Terminações Pré-Sinápticas/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Animais , Cromatografia Líquida de Alta Pressão , Bases de Dados de Proteínas , Hipocampo/química , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Transdução de Sinais , Espectrometria de Massas em Tandem
17.
BMC Syst Biol ; 3: 10, 2009 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-19154595

RESUMO

BACKGROUND: Studies of cellular signaling indicate that signal transduction pathways combine to form large networks of interactions. Viewing protein-protein and ligand-protein interactions as graphs (networks), where biomolecules are represented as nodes and their interactions are represented as links, is a promising approach for integrating experimental results from different sources to achieve a systematic understanding of the molecular mechanisms driving cell phenotype. The emergence of large-scale signaling networks provides an opportunity for topological statistical analysis while visualization of such networks represents a challenge. RESULTS: SNAVI is Windows-based desktop application that implements standard network analysis methods to compute the clustering, connectivity distribution, and detection of network motifs, as well as provides means to visualize networks and network motifs. SNAVI is capable of generating linked web pages from network datasets loaded in text format. SNAVI can also create networks from lists of gene or protein names. CONCLUSION: SNAVI is a useful tool for analyzing, visualizing and sharing cell signaling data. SNAVI is open source free software. The installation may be downloaded from: http://snavi.googlecode.com. The source code can be accessed from: http://snavi.googlecode.com/svn/trunk.


Assuntos
Transdução de Sinais , Software , Redes Reguladoras de Genes , Humanos , Redes e Vias Metabólicas , Biologia de Sistemas , Interface Usuário-Computador
18.
ScientificWorldJournal ; 7: 64-73, 2007 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-17982578

RESUMO

Morphine and related opiates are commonly used in the clinical management of various types of pain. However, the antinociceptive properties of morphine are often overshadowed by the development of tolerance and dependence following its chronic use. The mechanisms underlying opiate tolerance are not fully understood, but appear to involve numerous and complex physiological adaptations. Recently, a role for the heterodimerization of mu and delta opioid receptors in the development of morphine tolerance has been proposed. This novel mechanism could help us to understand several observations, such as the critical role of delta opioid receptor regulation, the impact of delta opioid receptor binding site occupancy, and the participation of beta-arrestin2, in the development of morphine tolerance.


Assuntos
Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Adaptação Biológica , Analgésicos Opioides/farmacologia , Animais , Tolerância a Medicamentos , Humanos , Transdução de Sinais
19.
Mol Cell Proteomics ; 6(1): 29-42, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17028301

RESUMO

Numerous studies have shown that drugs of abuse induce changes in protein expression in the brain that are thought to play a role in synaptic plasticity. Drug-induced plasticity can be mediated by changes at the synapse and more specifically at the postsynaptic density (PSD), which receives and transduces synaptic information. To date, the majority of studies examining synaptic protein profiles have focused on identifying the synaptic proteome. Only a handful of studies have examined the changes in synaptic profile by drug administration. We applied a quantitative proteomics analysis technique with the cleavable ICAT reagent to quantitate relative changes in protein levels of the hippocampal PSD in response to morphine administration. We identified a total of 102 proteins in the mouse hippocampal PSD. The majority of these were signaling, trafficking, and cytoskeletal proteins involved in synaptic plasticity, learning, and memory. Among the proteins whose levels were found to be altered by morphine administration, clathrin levels were increased to the largest extent. Immunoblotting and electron microscopy studies showed that this increase was localized to the PSD. Morphine treatment was also found to lead to a local increase in two other components of the endocytic machinery, dynamin and AP-2, suggesting a critical involvement of the endocytic machinery in the modulatory effects of morphine. Because alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are thought to undergo clathrin-mediated endocytosis, we examined the effect of morphine administration on the association of the AMPA receptor subunit, GluR1, with clathrin. We found a substantial decrease in the levels of GluR1 associated with clathrin. Taken together, these results suggest that, by causing a redistribution of endocytic proteins at the synapse, morphine modulates synaptic plasticity at hippocampal glutamatergic synapses.


Assuntos
Endocitose/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Morfina/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Proteômica , Proteínas de Transporte Vesicular/metabolismo , Sequência de Aminoácidos , Animais , Western Blotting , Cromatografia Líquida , Cadeias Pesadas de Clatrina/química , Cadeias Pesadas de Clatrina/ultraestrutura , Hipocampo/citologia , Hipocampo/ultraestrutura , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Morfina/administração & dosagem , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/química , Ligação Proteica/efeitos dos fármacos , Receptores de AMPA/metabolismo , Reprodutibilidade dos Testes , Proteínas de Transporte Vesicular/química
20.
J Pharmacol Exp Ther ; 318(2): 461-8, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16644901

RESUMO

Proteomic analyses of brain tissues are becoming an integral component of neuroscientific research. In particular, the essential role of the synapse in neurotransmission and plasticity has brought about extensive efforts to identify its protein constituents. Recent studies have used a combination of subcellular fractionation and proteomic techniques to identify proteins associated with different components of the synapse. Thus, a coherent map of the synapse proteome is rapidly emerging, and a timely review of these data is warranted. In the first part of this review, neuroproteomic techniques that have been used to analyze the synapse proteome are described. We then summarize the results from several recent proteomic analyses of mammalian synapses and discuss the similarities and differences in their profiling of synaptic proteins. Important advances in this field of research include the use of proteomics to analyze synaptic function and drug effects on synaptic proteins. This article presents an overview of proteomic analyses of the phosphorylation states of synaptic proteins and recent applications of neuroproteomic techniques to the study of drug addiction. Finally, we discuss the challenges in comparing proteomic studies of drug addiction and the future directions of this field in furthering our understanding of the molecular mechanisms underlying synaptic function and drug addiction.


Assuntos
Neurociências , Proteômica , Transtornos Relacionados ao Uso de Substâncias/genética , Sinapses/fisiologia , Animais , Perfilação da Expressão Gênica , Humanos , Receptores Pré-Sinápticos/genética , Receptores Pré-Sinápticos/fisiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
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