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AIM: To understand the progression of CLN1 disease and develop effective therapies we need to characterize early sites of pathology. Therefore, we performed a comprehensive evaluation of the nature and timing of early CLN1 disease pathology in the spinal cord, which appears especially vulnerable, and how this may affect behaviour. METHODS: We measured the spinal volume and neuronal number, and quantified glial activation, lymphocyte infiltration and oligodendrocyte maturation, as well as cytokine profile analysis during the early stages of pathology in Ppt1-deficient (Ppt1-/- ) mouse spinal cords. We then performed quantitative gait analysis and open-field behaviour tests to investigate the behavioural correlates during this period. RESULTS: We detected significant microglial activation in Ppt1-/- spinal cords at 1 month. This was followed by astrocytosis, selective interneuron loss, altered spinal volumes and oligodendrocyte maturation at 2 months, before significant storage material accumulation and lymphocyte infiltration at 3 months. The same time course was apparent for inflammatory cytokine expression that was altered as early as one month. There was a transient early period at 2 months when Ppt1-/- mice had a significantly altered gait that resembles the presentation in children with CLN1 disease. This occurred before an anticipated decline in overall locomotor performance across all ages. CONCLUSION: These data reveal disease onset 2 months (25% of life-span) earlier than expected, while spinal maturation is still ongoing. Our multi-disciplinary data provide new insights into the spatio-temporal staging of CLN1 pathogenesis during ongoing postnatal maturation, and highlight the need to deliver therapies during the presymptomatic period.
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Interneuronas/patología , Lipofuscinosis Ceroideas Neuronales/patología , Médula Espinal/patología , Tioléster Hidrolasas/deficiencia , Animales , Animales Recién Nacidos , Humanos , Ratones , Ratones NoqueadosRESUMEN
The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child's lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR/Cas9 gene editing technology. Three PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17 ± 1 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.
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Sistemas CRISPR-Cas , Modelos Animales de Enfermedad , Mutación , Lipofuscinosis Ceroideas Neuronales/patología , Fenotipo , Tioléster Hidrolasas/antagonistas & inhibidores , Animales , Femenino , Masculino , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Ovinos , Tioléster Hidrolasas/genéticaRESUMEN
INTRODUCTION: Desmopressin is commonly used to reduce bleeding in patients with mucocutaneous bleeding disorders and is available in both intravenous and intranasal forms. Given the variability in response to desmopressin at an individual level, its effectiveness should be assessed with a test dose prior to being advised for use. At this time, no trial has extensively compared the use of intranasal desmopressin to intravenous desmopressin. AIMS: To determine whether both forms of desmopressin are equally effective in yielding a positive response in laboratory assays in paediatric patients with von Willebrand disease or probable von Willebrand disease. METHODS: We evaluated medical record data for 58 patients who underwent desmopressin stimulation testing in our haematology clinic during a 1-year period. Data were collected on demographic information and haematologic laboratory assays prior to desmopressin administration and one hour following desmopressin. RESULTS: There was an absolute increase in von Willebrand antigen to levels appropriate for haemostasis following both forms of desmopressin, although this increase was significantly greater in the intravenous group compared to the intranasal group. There was also a significant absolute increase in Ristocetin Cofactor and Factor VIII levels following desmopressin in both groups. CONCLUSION: Both intravenous and intranasal forms of desmopressin produce a positive response during desmopressin stimulation testing and can be used to identify patients for whom this medication would be effective.
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Desamino Arginina Vasopresina/administración & dosificación , Desamino Arginina Vasopresina/uso terapéutico , Administración Intranasal , Administración Intravenosa , Niño , Femenino , Humanos , Masculino , Resultado del Tratamiento , Enfermedades de von Willebrand/tratamiento farmacológicoRESUMEN
Depression is a highly heterogeneous disorder. Accumulating evidence suggests biological and genetic differences between subtypes of depression that are homogeneous in symptom presentation. We aimed to evaluate differences in serum protein profiles between persons with atypical and melancholic depressive subtypes, and compare these profiles with serum protein levels of healthy controls. We used the baseline data from the Netherlands Study of Depression and Anxiety on 414 controls, 231 persons with a melancholic depressive subtype and 128 persons with an atypical depressive subtype for whom the proteomic data were available. Depressive subtypes were previously established using a data-driven analysis, and 171 serum proteins were measured on a multi-analyte profiling platform. Linear regression models were adjusted for several covariates and corrected for multiple testing using false discovery rate q-values. We observed differences in analytes between the atypical and melancholic subtypes (9 analytes, q<0.05) and between atypical depression and controls (23 analytes, q<0.05). Eight of the nine markers differing between the atypical and melancholic subtype overlapped with markers from the comparison between atypical subtype and controls (mesothelin, leptin, IGFBP1, IGFBP2, FABPa, insulin, C3 and B2M), and were mainly involved in cellular communication and signal transduction, and immune response. No markers differed significantly between the melancholic subtype and controls. To conclude, although some uncertainties exist in our results as a result of missing data imputation and lack of proteomic replication samples, many of the identified analytes are inflammatory or metabolic markers, which supports the notion of atypical depression as a syndrome characterized by metabolic disturbances and inflammation, and underline the importance and relevance of subtypes of depression in biological and genetic research, and potentially in the treatment of depression.
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Trastorno Depresivo/sangre , Proteómica , Adulto , Estudios de Casos y Controles , Complemento C3/metabolismo , Trastorno Depresivo/clasificación , Trastorno Depresivo/psicología , Proteínas de Unión a Ácidos Grasos/sangre , Femenino , Proteínas Ligadas a GPI/sangre , Humanos , Insulina/sangre , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Leptina/sangre , Modelos Lineales , Masculino , Mesotelina , Persona de Mediana Edad , Países Bajos , Microglobulina beta-2/sangreRESUMEN
Panic disorder with or without comorbid agoraphobia (PD/PDA) has been linked to an increased risk to develop subsequent depressive episodes, yet the underlying pathophysiology of these disorders remains poorly understood. We aimed to identify a biomarker panel predictive for the development of a depressive disorder (major depressive disorder and/or dysthymia) within a 2-year-follow-up period. Blood serum concentrations of 165 analytes were evaluated in 120 PD/PDA patients without depressive disorder baseline diagnosis (6-month-recency) in the Netherlands Study of Depression and Anxiety (NESDA). We assessed the predictive performance of serum biomarkers, clinical, and self-report variables using receiver operating characteristics curves (ROC) and the area under the ROC curve (AUC). False-discovery-rate corrected logistic regression model selection of serum analytes and covariates identified an optimal predictive panel comprised of tetranectin and creatine kinase MB along with patient gender and scores from the Inventory of Depressive Symptomatology (IDS) rating scale. Combined, an AUC of 0.87 was reached for identifying the PD/PDA patients who developed a depressive disorder within 2 years (n = 44). The addition of biomarkers represented a significant (p = 0.010) improvement over using gender and IDS alone as predictors (AUC = 0.78). For the first time, we report on a combination of biological serum markers, clinical variables and self-report inventories that can detect PD/PDA patients at increased risk of developing subsequent depressive disorders with good predictive performance in a naturalistic cohort design. After an independent validation our proposed biomarkers could prove useful in the detection of at-risk PD/PDA patients, allowing for early therapeutic interventions and improving clinical outcome.
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Forma MB de la Creatina-Quinasa/sangre , Depresión/sangre , Depresión/etiología , Lectinas Tipo C/sangre , Trastorno de Pánico/complicaciones , Adolescente , Adulto , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Proteínas de Unión al Calcio/metabolismo , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Escalas de Valoración Psiquiátrica , Curva ROC , Factores de Riesgo , Adulto JovenRESUMEN
Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95-1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86-0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71-0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82-0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.
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Esquizofrenia/diagnóstico , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Diagnóstico Precoz , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Factores de Riesgo , Esquizofrenia/sangre , Adulto JovenRESUMEN
Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention.
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Depresión/diagnóstico , Trastorno Depresivo Mayor/diagnóstico , Trastorno Distímico/diagnóstico , Trastornos Fóbicos/sangre , Adulto , Biomarcadores/sangre , Depresión/sangre , Depresión/etiología , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/etiología , Trastorno Distímico/sangre , Trastorno Distímico/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Fóbicos/complicaciones , Pronóstico , Escalas de Valoración Psiquiátrica , Factores de Riesgo , AutoinformeRESUMEN
AIMS/HYPOTHESIS: Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. METHODS: We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. RESULTS: Seventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10(-3)). All susceptibility loci had consistent direction of effects with the original study. CONCLUSIONS/INTERPRETATION: The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.
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Diabetes Mellitus Tipo 1/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Población Blanca/genética , Genotipo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. In discrete areas of the brain these vectors produced differential transduction patterns. AAV2/8 and 2/9 produced the most extensive gene delivery and had similar transduction profiles. All AAV pseudotypes preferentially transduced neurons whereas Ad5 transduced both neurons and glial cells. None of the vectors elicited any significant microglia-mediated immune response when compared with control uninjected mice. Whole-body imaging and immunohistological evaluation of brains 9 months post injection revealed long-term expression using these non-integrating vectors. These data will be useful in targeting genetic material to discrete or widespread areas of the fetal brain with the purpose of devising therapies for early neonatal lethal neurodegenerative disease and for studying brain development.
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Adenoviridae/genética , Encéfalo/metabolismo , Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos , Animales , Encéfalo/embriología , Femenino , Proteínas Fluorescentes Verdes/genética , Ratones , Neuroglía/metabolismo , Neuronas/metabolismo , Transducción GenéticaRESUMEN
AIMS: CLN8 deficiency underlies one of a group of devastating childhood neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The function of the CLN8 protein is currently unknown, but a role in lipid metabolism has been proposed. In human CLN8 diseased brains, alterations in lipid composition have been detected. To further investigate the connection of CLN8 to lipid metabolism, we characterized the lipid composition of early symptomatic Cln8-deficient mouse (Cln8(mnd)) brains. METHODS: For lipid profiling, Cln8(mnd) cerebral cortical tissue was analysed by liquid chromatography/mass spectrometry. Galactolipid synthesis was measured through enzyme activity and real-time mRNA expression analyses. Based on the findings, myelination and white matter integrity were studied by immunohistochemistry, stereological methods, electron microscopy and magnetic resonance imaging. The development of myelin-forming oligodendrocytes was also studied in vitro. RESULTS: Sphingolipid profiling showed a selective reduction in myelin-enriched galactolipids. The mRNA expression and activity of UDP-galactose:ceramide galactosyltransferase (CGT), the key enzyme in the galactolipid synthesis, was reduced in the Cln8(mnd) brain. Expression of oligodendrocyte markers suggests a maturation defect. The amount of myelin was reduced in 1-month-old Cln8(mnd) mice, but reached normal levels by 5 months of age. The level of Cln8 gene expression followed the developmental pattern of myelin formation and was high in primary oligodendrocytes. CONCLUSIONS: Taken together, these observations suggest that galactolipid deficiency and delayed myelin maturation characterize the early CLN8 disease pathogenesis through a maturation defect of oligodendrocytes.
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Axones , Proteínas de la Membrana/metabolismo , Lipofuscinosis Ceroideas Neuronales/metabolismo , Oligodendroglía/metabolismo , Animales , Axones/metabolismo , Axones/ultraestructura , Encéfalo/metabolismo , Encéfalo/patología , Diferenciación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas de la Membrana/deficiencia , Ratones , Ratones Noqueados , Vaina de Mielina/genética , Vaina de Mielina/patología , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/patología , Oligodendroglía/citología , Factores de TiempoRESUMEN
BACKGROUND: Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. METHODS: We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. FINDINGS: All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95]). INTERPRETATION: Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. FUNDING: Broncus Technologies.
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Broncoscopía , Stents Liberadores de Fármacos , Mediciones del Volumen Pulmonar , Enfisema Pulmonar/cirugía , Anciano , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel , Enfisema Pulmonar/fisiopatología , Volumen Residual , Capacidad Pulmonar Total , Capacidad VitalRESUMEN
Over the last ten years more reliable information regarding the risks and benefits of the use of albumin for fluid resuscitation has emerged. To determine what influence this has had on clinical practice, we sought to document albumin use (from mass of albumin supplied to hospitals) in 16 industrialised countries between 1995 and 2006. Data on national albumin and synthetic colloid use was sought from independent intensive care researchers and albumin issuers. The mass of albumin supplied per 10,000 persons on an annual basis by country and aggregated across the study countries was calculated. Volumes of synthetic colloid supplied per 10,000 persons were calculated. Data were obtained for 15 countries. Albumin use varied significantly between countries and throughout the observation period. Overall, aggregate albumin use decreased from a peak of 2.54 kg per 10,000 persons in 1995 to 1.40 kg per 10,000 persons in 1999; use has remained relatively constant since. Data on supply of synthetic colloids was available in only three countries and varied from 11.7 litres per 10,000 persons in Canada in 1995, to 231.8 litres per 10,000 persons in Denmark in 2004. Between 1995 and 1999 albumin use decreased and has been materially constant since; where data were available, use of synthetic colloids increased. Whether these practice changes have resulted in a net health gain or in harm requires further research.
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Albúminas/administración & dosificación , Fluidoterapia , Coloides/administración & dosificación , Humanos , Factores de TiempoRESUMEN
Recent advances in the statistical analysis of microsatellite data permit calculation of sex-specific dispersal rates through sex- and age-specific comparisons of genetic variation. This approach, developed for the analysis of data derived from co-dominant autosomal markers, should be applicable to a sex-specific marker such as mitochondrial DNA. To test this premise, we amplified a 449 bp control region DNA sequence from the mitochondrial genome of the collared peccary (Pecari tajacu), and estimated intra-class correlations among herds sampled from three Texas populations. Analyses on data partitioned by breeding group showed a clear signal of male-biased dispersal; sex-specific fixation indices associated with genetic variation among social groups within populations yielded values for females (F(GP)=0.91), which were significantly larger than values for males (F(GP)=0.24; P=0.0015). The same general pattern emerged when the analyses were conducted on age classes (albeit nonsignificantly), as well as categories of individuals that were predicted a posteriori to be dispersers (adult males) and philopatric (adult females and all immatures). By extending a previously published methodology based on biparentally inherited markers to matrilineally inherited haploid data, we calculated sex-specific rates of contemporary dispersal among social groups within populations (m(male symbol)=0.37). These results support the idea that mitochondrial DNA haplotype frequency data can be used to estimate sex-specific instantaneous dispersal rates in a social species.
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Artiodáctilos/genética , Artiodáctilos/fisiología , ADN Mitocondrial/genética , Variación Genética , Animales , Conducta Animal , ADN Mitocondrial/química , Femenino , Frecuencia de los Genes , Genética de Población , Haplotipos , Masculino , Análisis de Secuencia de ADN , Factores Sexuales , Texas , Factores de TiempoRESUMEN
The advent of genome-wide association (GWA) studies has revolutionized the detection of disease loci and provided abundant evidence for previously undetected disease loci that can be pooled together in meta-analysis studies or used to design follow-up studies. A total of 1715 SNPs from the Wellcome Trust Case Control Consortium GWA study of type I diabetes (T1D) were selected and a follow-up study was conducted in 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. In addition to the support for previously identified loci (PTPN22/1p13; ERBB3/12q13; SH2B3/12q24; CLEC16A/16p13; UBASH3A/21q22), evidence supporting two new and distinct chromosome locations associated with T1D was observed: FHOD3/18q12 (rs2644261, P=5.9 x 10(-4)) and Xp22 (rs5979785, P=6.8 x 10(-3); http://www.T1DBase.org). There was independent support for both SNPs in a GWA meta-analysis of 7514 cases and 9045 controls (P values=5.0 x 10(-3) and 6.7 x 10(-6), respectively). The chromosome 18q12 region contains four genes, none of which are obvious functional candidate genes. In contrast, the Xp22 SNP is located 30 kb centromeric of the functional candidate genes TLR8 and TLR7 genes. Both TLR8 and TLR7 are functional candidate genes owing to their key roles as pathogen recognition receptors and, in the case of TLR7, overexpression has been associated directly with murine autoimmune disease.
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Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Animales , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/inmunología , Femenino , Estudios de Seguimiento , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Ratones , Núcleo FamiliarRESUMEN
A candidate gene study was conducted on 10 established type II diabetes genes and 45 genes associated with autoimmune diseases, including type I diabetes (T1D), in a maximum of 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. Associations at P values <10(-3) were found for three known T1D regions at chromosomes 4q27, 12q13.2 and 12q24.13 (http://www.T1DBase.org). Support was obtained for a newly identified T1D candidate locus on chromosome 12q13.3-12q14.1 (rs1678536/KIF5A: P=8.1 x 10(-3); relative risk (RR) for minor allele=0.89, 95% CI=0.82-0.97), which has a separate association from the previously reported T1D candidate locus ERBB3/12q13.2-q13.3. Our new evidence adds to that previously published for the same gene region in a T1D case-control study (rs1678542; P=3.0 x 10(-4); odds ratio (OR)=0.92, 95% CI=0.88-0.96). This region, which contains many genes, has also been associated with rheumatoid arthritis.
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Enfermedades Autoinmunes/genética , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 4 , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Enfermedades Autoinmunes/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 2/inmunología , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
AIMS/HYPOTHESIS: We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003. METHODS: The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A-CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX-IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX-IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions. RESULTS: Only PPARG and HHEX-IDE showed any evidence of association with type 1 diabetes cases and controls (p = 0.004 and p = 0.003, respectively; p > 0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p = 0.003; p (combined) = 1.0 x 10(-4)). No SNPs showed evidence of interaction with any covariate (p > 0.05). CONCLUSIONS/INTERPRETATION: We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.
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Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , PPAR gamma/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
AIMS/HYPOTHESIS: The relationship between BP and microalbuminuria in young people with type 1 diabetes is not completely clear. As microalbuminuria is preceded by a gradual rise in albumin excretion within the normal range, we hypothesised that ambulatory BP (ABP) may be closely related to albumin excretion and progression to microalbuminuria. METHODS: ABP monitoring (ABPM) was performed in 509 young people with type 1 diabetes (age median [range]: 15.7 [10.7-22.6] years) followed with annual assessments of three early morning urinary albumin:creatinine ratios (ACRs) and HbA(1c). Systolic BP (SBP) and diastolic BP (DBP) and the nocturnal fall in BP were analysed in relation to ACR. RESULTS: All ABPM variables were significantly related to baseline log(10) ACR (p < 0.001). After the ABPM evaluation, 287 patients were followed for a median of 2.2 (1.0-5.5) years. ABP at baseline was independently related to mean ACR during follow-up. Nineteen initially normoalbuminuric patients developed microalbuminuria after 2.0 (0.2-4.0) years and their baseline daytime DBP was higher than in normoalbuminuric patients (p < 0.001). After adjusting for baseline ACR and HbA(1c), there was an 11% increased risk of microalbuminuria for each 1 mmHg increase in daytime DBP. Forty-eight per cent of patients were non-dippers for SBP and 60% for DBP; however, ACR was not different between dippers and non-dippers and there were no differences in the nocturnal fall in BP between normoalbuminuric and future microalbuminuric patients. CONCLUSIONS/INTERPRETATION: In this cohort of young people with type 1 diabetes, ABP was significantly related to ACR, and daytime DBP was independently associated with progression to microalbuminuria. Increasing albumin excretion, even in the normal range, may be associated with parallel rises in BP.
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Albúminas/metabolismo , Albuminuria/etiología , Albuminuria/fisiopatología , Presión Sanguínea/fisiología , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/orina , Femenino , Humanos , Masculino , Modelos de Riesgos ProporcionalesRESUMEN
Non-integrating lentiviral vectors show considerable promise for gene therapy applications as they persist as long-term episomes in non-dividing cells and diminish risks of insertional mutagenesis. In this study, non-integrating lentiviral vectors were evaluated for their use in the adult and fetal central nervous system of rodents. Vectors differentially pseudotyped with vesicular stomatitis virus, rabies and baculoviral envelope proteins allowed targeting of varied cell populations. Efficient gene delivery to discrete areas of the brain and spinal cord was observed following stereotactic administration. Furthermore, after direct in utero administration (E14), sustained and strong expression was observed 4 months into adulthood. Quantification of transduction and viral copy number was comparable when using non-integrating lentivirus and conventional integrating vector. These data support the use of non-integrating lentiviral vectors as an effective alternative to their integrating counterparts in gene therapy applications, and highlight their potential for treatment of inherited and acquired neurological disorders.
Asunto(s)
Encéfalo/metabolismo , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Lentivirus/genética , Animales , Cuerpo Estriado/metabolismo , Terapias Fetales/métodos , Terapia Genética/métodos , Lentivirus/fisiología , Ratones , Ratas , Médula Espinal/metabolismo , Técnicas Estereotáxicas , Transducción Genética , Integración ViralRESUMEN
Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser(307) association with T1D (P=3.46 x 10(-9)) and continued potential evidence for AITD (P=0.0345), we provide evidence for association of Gly307Ser with MS (P=4.20 x 10(-4)) and rheumatoid arthritis (RA) (P=0.017). The Ser(307) allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/genética , Enfermedades Autoinmunes/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Alelos , Enfermedades Autoinmunes/inmunología , Estudios de Casos y Controles , Cromosomas Humanos Par 18 , Intervalos de Confianza , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Exones , Frecuencia de los Genes , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Oportunidad Relativa , Mapeo Físico de CromosomaRESUMEN
As a result of genome-wide association studies in larger sample sets, there has been an increase in identifying genes that influence susceptibility to individual immune-mediated diseases, as well as evidence that some genes are associated with more than one disease. In this study, we tested 17 single nucleotide polymorphisms (SNP) from 16 gene regions that have been reported in several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), ankylosing spondylitis (AS) and Crohn's disease (CD) to determine whether the variants are also associated with type 1 diabetes (T1D). In up to 8010 cases and 9733 controls we found some evidence for an association with T1D in the regions containing genes: 2q32/STAT4, 17q21/STAT3, 5p15/ERAP1 (ARTS1), 6q23/TNFAIP3 and 12q13/KIF5A/PIP4K2C with allelic P-values ranging from 3.70 x 10(-3) to 3.20 x 10(-5). These findings extend our knowledge of susceptibility locus sharing across different autoimmune diseases, and provide convincing evidence that the RA/SLE locus 6q23/TNFAIP3 is a newly identified T1D locus.