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1.
Hum Mol Genet ; 22(10): 2119-27, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23314186

RESUMO

With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(-16), ß = -0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(-7), ß = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(-16), ß = -0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(-7), ß = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(-17), ß = -0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.


Assuntos
Aterosclerose/sangue , Aterosclerose/genética , Cromossomos Humanos/genética , Estudo de Associação Genômica Ampla , Contagem de Leucócitos , Adulto , Idoso , Cromossomos Humanos/metabolismo , Feminino , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Humanos , Integrina alfa4/genética , Integrina alfa4/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Monócitos , Mutação de Sentido Incorreto , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo
2.
J Biomed Inform ; 52: 28-35, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24534443

RESUMO

The last decade has seen an exponential growth in the quantity of clinical data collected nationwide, triggering an increase in opportunities to reuse the data for biomedical research. The Vanderbilt research data warehouse framework consists of identified and de-identified clinical data repositories, fee-for-service custom services, and tools built atop the data layer to assist researchers across the enterprise. Providing resources dedicated to research initiatives benefits not only the research community, but also clinicians, patients and institutional leadership. This work provides a summary of our approach in the secondary use of clinical data for research domain, including a description of key components and a list of lessons learned, designed to assist others assembling similar services and infrastructure.


Assuntos
Pesquisa Biomédica/métodos , Sistemas de Gerenciamento de Base de Dados , Informática Médica/métodos , Registros Eletrônicos de Saúde , Humanos
3.
Hum Genet ; 131(4): 639-52, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22037903

RESUMO

White blood cell count (WBC) is unique among identified inflammatory predictors of chronic disease in that it is routinely measured in asymptomatic patients in the course of routine patient care. We led a genome-wide association analysis to identify variants associated with WBC levels in 13,923 subjects in the electronic Medical Records and Genomics (eMERGE) Network. We identified two regions of interest that were each unique to subjects of genetically determined ancestry to the African continent (AA) or to the European continent (EA). WBC varies among different ancestry groups. Despite being ancestry specific, these regions were identifiable in the combined analysis. In AA subjects, the region surrounding the Duffy antigen/chemokine receptor gene (DARC) on 1q21 exhibited significant association (p value = 6.71e-55). These results validate the previously reported association between WBC and of the regulatory variant rs2814778 in the promoter region, which causes the Duffy negative phenotype (Fy-/-). A second missense variant (rs12075) is responsible for the two principal antigens, Fya and Fyb of the Duffy blood group system. The two variants, consisting of four alleles, act in concert to produce five antigens and subsequent phenotypes. We were able to identify the marginal and novel interaction effects of these two variants on WBC. In the EA subjects, we identified significantly associated SNPs tagging three separate genes in the 17q21 region: (1) GSDMA, (2) MED24, and (3) PSMD3. Variants in this region have been reported to be associated with WBC, neutrophil count, and inflammatory diseases including asthma and Crohn's disease.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla/métodos , Contagem de Leucócitos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , População Negra/genética , Sistema do Grupo Sanguíneo Duffy/genética , Feminino , Frequência do Gene , Genoma Humano/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Humanos , Masculino , Complexo Mediador/genética , Prontuários Médicos/estatística & dados numéricos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Complexo de Endopeptidases do Proteassoma/genética , Receptores de Superfície Celular/genética , População Branca/genética , População Branca/estatística & dados numéricos
4.
J Am Med Inform Assoc ; 21(2): 337-44, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24045907

RESUMO

OBJECTIVE: Common chronic diseases such as hypertension are costly and difficult to manage. Our ultimate goal is to use data from electronic health records to predict the risk and timing of deterioration in hypertension control. Towards this goal, this work predicts the transition points at which hypertension is brought into, as well as pushed out of, control. METHOD: In a cohort of 1294 patients with hypertension enrolled in a chronic disease management program at the Vanderbilt University Medical Center, patients are modeled as an array of features derived from the clinical domain over time, which are distilled into a core set using an information gain criteria regarding their predictive performance. A model for transition point prediction was then computed using a random forest classifier. RESULTS: The most predictive features for transitions in hypertension control status included hypertension assessment patterns, comorbid diagnoses, procedures and medication history. The final random forest model achieved a c-statistic of 0.836 (95% CI 0.830 to 0.842) and an accuracy of 0.773 (95% CI 0.766 to 0.780). CONCLUSIONS: This study achieved accurate prediction of transition points of hypertension control status, an important first step in the long-term goal of developing personalized hypertension management plans.


Assuntos
Gerenciamento Clínico , Registros Eletrônicos de Saúde , Hipertensão/terapia , Anti-Hipertensivos/uso terapêutico , Doença Crônica , Humanos , Modelos Teóricos , Prognóstico
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