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BACKGROUND: The identification of recent human immunodeficiency virus (HIV) 1 infections among people with new HIV diagnoses is important to both tailoring and assessing the impact of HIV-1 prevention strategies. METHODS: We developed a multiplexed Primer ID-next-generation sequencing approach to identify recent infections by measuring the intrahost viral diversity over multiple regions of the HIV-1 genome, in addition to detecting drug resistance mutations (DRMs) and phylogenetically linked clusters. We summarize the field implementation of this all-in-one platform among persons with newly diagnosed HIV-1 by the North Carolina State Laboratory of Public Health in 2018. RESULTS: Overall, recent infection was identified in 94 (35%) of 268 patients with new HIV diagnoses. People <30 years old, and people who inject drugs were more likely to have diagnoses of recent infection. The reverse-transcriptase region K103N was the most commonly detected DRM (prevalence, approximately 15%). We found a total of 28 clusters, and persons with recent infection were more likely to be cluster members than were those with chronic infections (P = .03). CONCLUSIONS: We demonstrate the rapid identification of recent infection and pretreatment DRMs coupled with cluster analysis that will allow prioritization of linkage to care, treatment, and prevention interventions to those at highest risk of onward transmission.
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Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , Adulto , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , VIH-1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , North Carolina/epidemiología , Infección PersistenteRESUMEN
We report here the complete genome sequence of the facultative predatory bacterium Ensifer adhaerens strain Casida A. The genome was assembled into three circular contigs, with a main chromosome as well as two large secondary replicons, that totaled 7,267,502 bp with 6,641 predicted open reading frames.
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OBJECTIVES: Schizophrenia is an highly heritable complex disorder with a significant impact on public health. A variety of antipsychotics are available for treatment of the disorder and individual response to treatment is variable. To date, only a limited number of potential candidate genes have been examined for genetic association with treatment response. As there is lack of understanding of disease etiology and variation in treatment response, a large number of additional genes are potential targets for investigation. A variety of strategies for selecting candidate genes for further investigation are available and in most cases information used is weighed and ranked intuitively by the investigator. We sought to find genes that may influence treatment response in a less biased manner, after integrating heterogeneous data sources related to schizophrenia. METHODS: A method to select liability and treatment response candidate genes for schizophrenia using multiple data sets was constructed. The method successfully selected DTNBP1, a strong candidate gene for schizophrenia. We then evaluated novel genes picked by the method. Thirty-six single nucleotide polymorphisms in two genes engrailed 1 (EN1) and secretin receptor (SCTR) were genotyped in the Clinical Antipsychotic Trials of Intervention Effectiveness study sample. Outcomes analyzed were the Positive and Negative Syndrome Scale and six different neurocognitive measures. RESULTS: Several of the seven single nucleotide polymorphisms genotyped in the EN1 gene were associated with schizophrenia symptoms (smallest P value=0.0061) and the effects of antipsychotics on symptoms (smallest P value=2.4x10). The estimated probabilities of being a false discovery were 0.14 for symptoms and 0.0012 for drug response. CONCLUSION: These findings show that EN1 may influence individual variation in response to antipsychotics. In addition, model-based data integration of schizophrenia-related data seems to improve the prior probability of selecting genes that have an effect on antipsychotics response.
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Antipsicóticos/uso terapéutico , Proteínas de Homeodominio/genética , Modelos Biológicos , Polimorfismo de Nucleótido Simple/genética , Receptores Acoplados a Proteínas G/genética , Receptores de la Hormona Gastrointestinal/genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Selección Genética , HumanosRESUMEN
BACKGROUND: Several lines of evidence indicate that Regulator of G Protein Signaling 4 (RGS4) contributes to schizophrenia vulnerability. RGS4 is one of a family of molecules that modulate signaling via G-protein coupled receptors. Five genes encoding members of this family (RGS2, RGS4, RGS5, RGS8 and RGS16) map to chromosome 1q23.3-1q31. Due to overlapping cellular functions and chromosomal proximity, we hypothesized that multiple RGS genes may contribute to schizophrenia severity and treatment responsiveness. METHODS: Subjects were 750 individuals with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Inferred ancestries were: 221 (30%) 'Africa only', 422 (56%) 'Europe only' and 107 (14%) 'Other'. Fifty-nine single nucleotide polymorphisms (SNPs) in or near the RGS5, RGS16, RGS8 and RGS2 genes were genotyped. Multiple linear regression was used to analyze association of markers with Positive and Negative Symptoms Scale (PANSS) total scores at baseline and throughout antipsychotic treatment. RESULTS: RGS5 marker rs10799902 was associated with altered baseline PANSS total score in both the Africa only (P=0.0440) and Europe only (P=0.0143) strata, although neither association survived multiple comparisons correction. A common five-marker haplotype of the RGS2 gene was associated with more severe baseline PANSS total score in the Europe only strata (global P=0.0254; haplotype-specific P=0.0196). In contrast to RGS4, none of the markers showed association with antipsychotic treatment response. CONCLUSIONS: RGS2 and RGS5 genotypes predicted severity of baseline symptoms in schizophrenia. Although these analyses are exploratory and replication is required, these data suggest a possible role for multiple RGS proteins in schizophrenia.
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Predisposición Genética a la Enfermedad , Proteínas RGS/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Análisis de Varianza , Población Negra , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Escalas de Valoración Psiquiátrica , Población BlancaRESUMEN
BACKGROUND: Genetic association studies, including a large meta-analysis, report association of regulator of G protein signaling 4 (RGS4) with schizophrenia in the context of heterogeneity. The central role of RGS4 in regulating signaling via Gi/o coupled neurotransmitter receptors led us to hypothesize that there may be RGS4 genotypes predictive of specific disease phenotypes and antipsychotic treatment responses. METHODS: Subjects were 678 individuals with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Among the 678 subjects, the inferred ancestries were 198 (29%) "Africa only," 397 (59%) "Europe only," and 83 (12%) "Other." Eight single nucleotide polymorphisms (SNPs) spanning RGS4 were genotyped. Multiple linear regression was used to analyze association of RGS4 markers with Positive and Negative Symptoms Scale (PANSS) scores at baseline and throughout antipsychotic treatment. RESULTS: Two consecutive markers within RGS4, rs2661319 and rs2842030, were associated with more severe baseline PANSS total score. Treatment with perphenazine was more effective than treatment with quetiapine (p = .010) or ziprasidone (p = .002) in individuals of inferred African ancestry and homozygous for the rs951439 C allele. CONCLUSIONS: RGS4 genotypes predicted both the severity of baseline symptoms and relative responsiveness to antipsychotic treatment. Although these analyses are exploratory and replication is required, these data provide support for RGS4 in schizophrenia pathogenesis and suggest a functional role for RGS4 in differential antipsychotic treatment efficacy of schizophrenia.
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Predisposición Genética a la Enfermedad , Farmacogenética , Polimorfismo de Nucleótido Simple , Proteínas RGS/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Análisis de Varianza , Antipsicóticos/uso terapéutico , Dibenzotiazepinas/uso terapéutico , Etnicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Perfenazina/uso terapéutico , Escalas de Valoración Psiquiátrica , Fumarato de Quetiapina , Estudios Retrospectivos , Esquizofrenia/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: Previous research has shown conflicting results for the significance of five v-akt murine thymoma viral oncogene homolog 1 (AKT1) single-nucleotide polymorphisms (SNPs) to the aetiology of schizophrenia. Neurocognition is a plausible endophenotype for schizophrenia and it was reasoned that the lack of agreement might be due to variability in neurocognition across studies. Therefore, the association of genetic variation in AKT1 with neurocognition was investigated in patients with schizophrenia. METHODS: The same five SNPs used in previous studies of the etiology of schizophrenia (rs2494732, rs2498799, rs3730358, rs1130214, [corrected] and rs3803300) were genotyped in 641 individuals with schizophrenia who had participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. The primary dependent variable was a neurocognitive composite score and exploratory analyses investigated five domain scores (processing speed, reasoning, verbal memory, working memory, and vigilance). RESULTS: There were no significant asymptotic or empirical associations between any SNP and the neurocognitive composite score. The authors also investigated the association of five-SNP haplotypes with the neurocognitive composite score. A marginally significant association was observed for the neurocognitive composite score with one of the five-SNP haplotypes (global score statistic 19.51, df = 9, permutation p = 0.02). Exploratory analyses of five domain scores (processing speed, reasoning, verbal memory, working memory, and vigilance) were non-significant for all five SNPs. CONCLUSION: Results published to date for an association between genetic variation in AKT1 with schizophrenia are inconsistent. The results suggest that the AKT1 markers studied are not associated with neurocognition in schizophrenia, and do not support unassessed variation in neurocognitive scores as a reason for this discrepancy.
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Encéfalo/fisiopatología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Proteínas Proto-Oncogénicas c-akt/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Adolescente , Adulto , Anciano , Trastornos del Conocimiento/diagnóstico , Femenino , Genómica , Genotipo , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Grupos Raciales/genética , Esquizofrenia/terapia , Resultado del TratamientoRESUMEN
We previously reported a linkage region on chromosome 10q for age-at-onset (AAO) of Alzheimer (AD) and Parkinson (PD) diseases. Glutathione S-transferase, omega-1 (GSTO1) and the adjacent gene GSTO2, located in this linkage region, were then reported to associate with AAO of AD and PD. To examine whether GSTO1 and GSTO2 (hereafter referred to as GSTO1h) are responsible for the linkage evidence, we identified 39 families in AD that lead to our previous linkage and association findings. The evidence of linkage and association was markedly diminished after removing these 39 families from the analyses, thus providing support that GSTO1h drives the original linkage results. The maximum average AAO delayed by GSTO1h SNP 7-1 (rs4825, A nucleotide) was 6.8 (+/-4.41) years for AD and 8.6(+/-5.71) for PD, respectively. This is comparable to the magnitude of AAO difference by APOE-4 in these same AD and PD families. These findings suggest the presence of genetic heterogeneity for GSTO1h's effect on AAO, and support GSTO1h's role in modifying AAO in these two disorders.
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Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/epidemiología , Pruebas Genéticas/métodos , Glutatión Transferasa/genética , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/epidemiología , Medición de Riesgo/métodos , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Análisis Mutacional de ADN/métodos , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Inflammatory processes have been implicated in the cascade of events that lead to nerve cell death. In the nervous system, a number of genes involved in inflammation pathways are regulated post-transcriptionally via the interaction of their mRNAs with specific RNA-binding Hu proteins, the vertebrate homologues of the Drosophila ELAV (for embryonic lethal abnormal vision). The gene encoding ELAVL4, a member of the Hu family of proteins, is located 2 Mb from the chromosome 1p linkage region peak for age-at-onset (AAO) of Parkinson disease (PD) (LOD = 3.41). Nine single-nucleotide polymorphisms (SNPs) in ELAVL4 were genotyped for 266 multiplex families (1,223 samples). Additional genotyping in 377 singleton families was performed for a subset of five SNPs (SNPs 1-5) that were not in linkage disequilibrium. SNP 2 (located in the first intron of ELAVL4) showed a strong significant association with AAO of PD (P = 0.006), and SNP 5 (a coding SNP in ELAVL4) showed a moderately significant association (P = 0.035). Haplotype analysis revealed that the A-C haplotype at SNPs 2 and 3 has the strongest significant association with AAO (P = 0.0001) among all combinations of two or three loci. The A-C haplotype remained significant for AAO after the inclusion of the C allele at SNP 5 to this haplotype (A-C-C haplotype, P = 0.00018). Although SNP 5 was found to associate with PD risk in the early-onset subset of PD families (at least one affected with AAO <40 years, 60 families), we believe that it is a by-product of its association with AAO. Taken together, these results suggest a potential role for ELAVL4 as a modifier gene for AAO of PD.