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1.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
2.
J Neuroimaging ; 29(4): 499-505, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074062

RESUMO

BACKGROUND AND PURPOSE: In vivo detection of ß-amyloid (Aß) plaques in Alzheimer's disease (AD) is now possible with 11 C-PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4-1.5 has been used to categorize at-risk subjects as "amyloid-positive" and "amyloid-negative." It has been suggested that this threshold is too conservative and may miss early amyloid pathology. We investigated the relationship between conventional and lower baseline 11 C-PiB PET thresholds for raised amyloid load and the subsequent clinical and radiological progression of mild cognitive impairment (MCI) cases longitudinally. METHODS: We serially determined the cortical amyloid load with 11 C-PiB PET of 44 MCI subjects over 2 years and compared findings with those for 12 healthy controls (HC) and 5 AD cases. RESULTS: Twenty-four subjects were classified as normal at baseline with mean cortical PiB standard uptake value ratios (SUVR) between 1.2 and 1.5. Their cognitive status remained stable over time. Three of these cases increased their amyloid load above a threshold of 1.5 over 2 years. Twenty-seven "raised amyloid" MCI cases with baseline cortical SUVRs above 1.5, showed deteriorating cognition. Note that 50% of these cases converted clinically to AD during the follow-up period. CONCLUSION: Use of a PiB SUVR threshold of >1.5 for raised amyloid missed 14.3% of MCI cases who likely had Thal stage 1 or 2 pathology and showed a progressive amyloid increase over 2 years. Lowering the threshold for abnormality to 1.3 abolished all false negatives but resulted in 75% of HCs being falsely diagnosed as raised amyloid subjects.

3.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
4.
Neurobiol Dis ; 124: 479-488, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30590179

RESUMO

Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.

5.
Sci Rep ; 8(1): 16486, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405140

RESUMO

Schizophrenia is a common and severe mental disorder arising from complex gene-environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic susceptibility and phenotypic relevance to schizophrenia (Brd1+/- mice) using postmortem 3D MR imaging coupled with histology, immunostaining and regional mRNA marker analysis. In agreement with recent large-scale schizophrenia neuroimaging studies, Brd1+/- mice displayed subcortical abnormalities, including volumetric reductions of amygdala and striatum. Interestingly, we demonstrate that structural alteration in striatum correlates with a general loss of striatal neurons, differentially impacting subpopulations of medium-sized spiny neurons and thus potentially striatal output. Akin to parvalbumin interneuron dysfunction in patients, a decline in parvalbumin expression was noted in the developing cortex of Brd1+/- mice, mainly driven by neuronal loss within or near cortical layer V, which is rich in corticostriatal projection neurons. Collectively, our study highlights the translational value of the Brd1+/- mouse as a pre-clinical tool for schizophrenia research and provides novel insight into its developmental, structural, and cellular pathology.

6.
Microvasc Res ; 2018 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30144413

RESUMO

The blood-brain barrier consists of a tightly sealed monolayer of endothelial cells being vital in maintaining a stable intracerebral microenvironment. The barrier is receptive to leakage upon exposure to environmental factors, like hypoxia, and its disruption has been suggested as a constituent in the pathophysiology of both neurological and psychiatric disorders. The schizophrenia associated ZEB1 gene encodes a transcription factor susceptible to transcriptional control by a hypoxia induced factor, HIF1A, known to be implicated in blood-brain barrier dysfunction. However, whether ZEB1 is also implicated in maintaining blood-brain barrier integrity upon hypoxia is unknown. Here we assessed Hif1a, Zo1 and Zeb1 mRNA expression and ZO1 protein abundancy in a mimetic system of the in vivo blood-brain barrier comprising mouse brain endothelial cells subjected to the norm- and proven hypoxic conditions. Despite that, Hif1a mRNA expression was significantly increased, clearly indicating that the oxygen-deprived environment introduced a hypoxia response in the cells, we found no hypoxia-induced changes in neither ZO1 abundancy nor in the expression of Zo1 and Zeb1 mRNA. However, independent of hypoxia status, we found that Zeb1 and Zo1 mRNA expression is highly correlated. Further studies are warranted that investigate the implication of the ZEB1/ZO1 axis in blood-brain barrier maintenance under different physiological conditions.

8.
Am J Transl Res ; 9(7): 3517-3527, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28804568

RESUMO

The clinical utility of Traditional Chinese Medicine (TCM) herbs/roots extracts in osteoporosis (OP) and osteoarthritis (OA) has been described in multiple reports, but there have been few studies of TCM for preventing bone loss and cartilage degradation simultaneously. Six-month-old female Sprague-Dawley rats each were subjected to ovariectomized (OVX) or sham surgery and treated orally once daily with herbal extracts or vehicle. Body weight was recorded weekly, and blood samples were collected from fasting animals at different time points. Biochemical markers of bone resorption and cartilage degradation were analyzed. Changes in bone mineral density and calcium content were determined in the femoral center and femoral telocentric end of rats. Out of 56 TCM herbs/roots extracts, only kudzu root demonstrated consistent joint protective effects. OVX resulted in a marked increase in bone resorption and cartilage degradation, which could be significantly reversed by kudzu after three weeks of treatment. Compared to vehicle, kudzu induced a significant increase in bone mineral density in the femoral center and femoral telocentric end, and calcium content. The results show that kudzu exerts direct effects on articular cartilage in the OVX rat and can effectively prevent the acceleration of cartilage degradation induced by ovariectomy. Moreover, kudzu has demonstrated positive effects on metabolic health (cause a weight reduction) and may represent a possible treatment for OP and OA with high body mass index. Further studies are needed to investigate the potential effects of kudzu root in postmenopausal women.

9.
Neurobiol Learn Mem ; 141: 44-52, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28341151

RESUMO

Schizophrenia is a debilitating brain disorder characterized by disturbances of emotion, perception and cognition. Cognitive impairments predict functional outcome in schizophrenia and are detectable even in the prodromal stage of the disorder. However, our understanding of the underlying neurobiology is limited and procognitive treatments remain elusive. We recently demonstrated that mice heterozygous for an inactivated allele of the schizophrenia-associated Brd1 gene (Brd1+/- mice) display behaviors reminiscent of schizophrenia, including impaired social cognition and long-term memory. Here, we further characterize performance of these mice by following the preclinical guidelines recommended by the 'Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)' and 'Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS)' initiatives to maximize translational value. Brd1+/- mice exhibit relational encoding deficits, compromised working and long term memory, as well as impaired executive cognitive functioning with cognitive behaviors relying on medial prefrontal cortex being particularly affected. Akin to patients with schizophrenia, the cognitive deficits displayed by Brd1+/- mice are not global, but selective. Our results underline the value of Brd1+/- mice as a promising tool for studying the neurobiology of cognitive deficits in schizophrenia.


Assuntos
Transtornos Cognitivos/genética , Cognição/fisiologia , Função Executiva/fisiologia , Histona Acetiltransferases/genética , Esquizofrenia/genética , Alelos , Animais , Comportamento Animal/fisiologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Heterozigoto , Masculino , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Knockout , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia
10.
PLoS One ; 12(1): e0170121, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28095495

RESUMO

The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced BRD1 expression. Insights into the transcriptional regulation of BRD1 and the pathogenic mechanisms associated with BRD1 risk variants, however, remain sparse. By studying transcripts in human HeLa and SH-SY5Y cells we provide evidence for differences in relative expression of BRD1 transcripts with three alternative 5' UTRs (exon 1C, 1B, and 1A). We further show that expression of these transcript variants covaries negatively with DNA methylation proportions in their upstream promoter regions suggesting that promoter usage might be regulated by DNA methylation. In line with findings that the risk allele of the rs138880 SNP in the BRD1 promoter region correlates with reduced BRD1 expression, we find that it is also associated with moderate regional BRD1 promoter hypermethylation in both adipose tissue and blood. Importantly, we demonstrate by inspecting available DNA methylation and expression data that these regions undergo changes in methylation during fetal brain development and that differences in their methylation proportions in fetal compared to postnatal frontal cortex correlate significantly with BRD1 expression. These findings suggest that BRD1 may be dysregulated in both the developing and mature brain of risk allele carriers. Finally, we demonstrate that commonly used mood stabilizers Lithium, Valproate, and Carbamazepine affect the expression of BRD1 in SH-SY5Y cells. Altogether this study indicates a link between genetic risk and epigenetic dysregulation of BRD1 which raises interesting perspectives for targeting the mechanisms pharmacologically.


Assuntos
Adenocarcinoma/genética , Metilação de DNA , Neuroblastoma/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Esquizofrenia/genética , Adenocarcinoma/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Feto/metabolismo , Feto/patologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Células HeLa , Humanos , Neuroblastoma/patologia , Esquizofrenia/patologia
11.
Biol Psychiatry ; 82(1): 62-76, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27837920

RESUMO

BACKGROUND: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative. METHODS: This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1+/- mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters. RESULTS: Brd1+/- mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1+/- and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D2 [Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]). CONCLUSIONS: Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.


Assuntos
Comportamento Animal/fisiologia , Expressão Gênica/genética , Histona Acetiltransferases/fisiologia , Esquizofrenia/genética , Transmissão Sináptica/genética , Acetilação , Animais , Animais Geneticamente Modificados/genética , Corpo Estriado/metabolismo , Dopamina/metabolismo , Histona Acetiltransferases/genética , Histonas/metabolismo , Interneurônios/fisiologia , Camundongos , Serotonina/metabolismo
12.
Bone ; 91: 122-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27462009

RESUMO

This randomized, double-blind, placebo-controlled phase III study was conducted to assess the efficacy and safety of oral calcitonin (SMC021) for the treatment of postmenopausal osteoporosis. A total of 4665 postmenopausal women with osteoporosis were randomized 1:1 to receive calcium and vitamin D plus either SMC021 tablets (0.8mg/d) or placebo for 36months. The primary endpoint was the proportion of patients with a new vertebral fracture. The two groups were well balanced at baseline with regards to demographic and clinical data. No effect of SMC021 on preventing new vertebral fractures was observed, nor was any effect seen on new hip or non-vertebral fractures. Women receiving SMC021 had a mean 1.02% (±0.12%) increase in lumbar spine bone mineral density (BMD) compared with a mean 0.18% (±0.12%) increase in the placebo group by the end of the study (p<0.0001). Similarly, small increases in BMD were observed at the femoral neck and hip in both groups. Levels of the biomarkers of bone turnover, urinary CTX-I and CTX-II, were 15% lower in the SMC021 group than in the placebo arm at 12 and 24months, but not at 36months. No change in quality of life between groups, assessed by the Qualeffo-14 questionnaire, was observed in either group between baseline and month 36. Pharmacokinetics analysis confirmed exposure to SMC021, but the drug levels were markedly lower than expected. Approximately 92% of subjects in each treatment group experienced an adverse event (AE), the majority of which were mild or moderate in intensity. AEs associated with SMC021 were primarily of gastrointestinal origin and included nausea, vomiting and abdominal pain, as well as hot flushes which were the reason for the slightly higher drop-out rate in the active treatment arm compared to placebo. The number of severe AEs was low in both groups. Thirty-five deaths were reported but none were considered treatment-related. Due to the lack of efficacy in preventing fractures, the development of the orally formulated calcitonin was terminated despite the promising results in earlier studies.


Assuntos
Calcitonina/efeitos adversos , Calcitonina/uso terapêutico , Cálcio/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Vitamina D/uso terapêutico , Administração Oral , Idoso , Biomarcadores/metabolismo , Densidade Óssea , Remodelação Óssea/efeitos dos fármacos , Calcitonina/administração & dosagem , Calcitonina/farmacocinética , Demografia , Método Duplo-Cego , Feminino , Humanos , Incidência , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/complicações , Fraturas por Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/fisiopatologia , Placebos , Qualidade de Vida , Fatores de Risco , Resultado do Tratamento
13.
BMC Genomics ; 16: 548, 2015 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-26208977

RESUMO

BACKGROUND: Massively parallel cDNA sequencing (RNA-seq) experiments are gradually superseding microarrays in quantitative gene expression profiling. However, many biologists are uncertain about the choice of differentially expressed gene (DEG) analysis methods and the validity of cost-saving sample pooling strategies for their RNA-seq experiments. Hence, we performed experimental validation of DEGs identified by Cuffdiff2, edgeR, DESeq2 and Two-stage Poisson Model (TSPM) in a RNA-seq experiment involving mice amygdalae micro-punches, using high-throughput qPCR on independent biological replicate samples. Moreover, we sequenced RNA-pools and compared their results with sequencing corresponding individual RNA samples. RESULTS: False-positivity rate of Cuffdiff2 and false-negativity rates of DESeq2 and TSPM were high. Among the four investigated DEG analysis methods, sensitivity and specificity of edgeR was relatively high. We documented the pooling bias and that the DEGs identified in pooled samples suffered low positive predictive values. CONCLUSIONS: Our results highlighted the need for combined use of more sensitive DEG analysis methods and high-throughput validation of identified DEGs in future RNA-seq experiments. They indicated limited utility of sample pooling strategies for RNA-seq in similar setups and supported increasing the number of biological replicate samples.


Assuntos
DNA Complementar/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de RNA , Animais , Camundongos , Software
14.
Proc Natl Acad Sci U S A ; 112(7): 2157-62, 2015 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-25646469

RESUMO

Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1's function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.


Assuntos
Linfócitos B/metabolismo , Proteína BRCA1/genética , Reparo do DNA , Switching de Imunoglobulina , Recombinação Genética , Humanos
15.
Bipolar Disord ; 17(2): 205-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25053281

RESUMO

OBJECTIVES: Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.3) with psychiatric disorders has been reported. We aimed to narrow down these chromosomal breakpoint regions and to investigate the associations between single nucleotide polymorphisms within these regions and BD as well as schizophrenia (SZ) in large genome-wide association study samples. METHODS: We cross-linked Danish psychiatric and cytogenetic case registers to identify an individual with both t(9;17)(q33.2;q25.3) and BD. Fluorescent in situ hybridization was employed to map the chromosomal breakpoint regions of this proband. We accessed the Psychiatric Genomics Consortium BD (n = 16,731) and SZ (n = 21,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes. RESULTS: Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213 (RNF213), and regulatory-associated protein of mammalian target of rapamycin (mTOR) (RPTOR)] were found to be located within the 17q25.3 breakpoint region. NPTX1 was significantly associated with BD (p = 0.004), while ENDOV was significantly associated with SZ (p = 0.0075) after Bonferroni correction. CONCLUSIONS: Prior linkage evidence and our findings suggest NPTX1 as a novel candidate gene for BD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Transtorno Bipolar/genética , Proteína C-Reativa/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Ubiquitina-Proteína Ligases/genética , Adenosina Trifosfatases , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 9/genética , Família , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , Proteína Regulatória Associada a mTOR , Translocação Genética/genética
16.
Biomark Med ; 8(5): 713-31, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25123039

RESUMO

The identification and clinical demonstration of efficacy and safety of osteo- and chondro-protective drugs are met with certain difficulties. During the last few decades, the pharmaceutical industry has, in the field of rheumatology, experienced disappointments associated with the development of disease modification. Today, the vast amount of patients suffering from serious, chronic joint diseases can only be offered treatments aimed at improving symptoms, such as pain and acute inflammation, and are not aimed at protecting the joint tissue. This huge, unmet medical need has been the driver behind the development of improved analytical techniques allowing better and more efficient clinical trial design, implementation and analysis. With this review, we aim to provide a brief and general overview of biochemical markers of joint tissue, with special focus on neoepitopes. Furthermore, we highlight recent studies applying biochemical markers in joint degenerative diseases. These disorders, including osteoarthritis, rheumatoid arthritis and spondyloarthropathies, are the most predominant disorders in Europe and the USA, and have enormous socioeconomical impact.


Assuntos
Cartilagem/metabolismo , Articulações/metabolismo , Animais , Biomarcadores/metabolismo , Descoberta de Drogas , Saúde , Humanos , Artropatias/tratamento farmacológico , Artropatias/metabolismo
17.
Menopause ; 20(5): 578-86, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23615651

RESUMO

OBJECTIVE: Joint health is affected by local and systemic hormones. It is well accepted that systemic factors regulate the metabolism of joint tissues, and that substantial cross-talk between tissues actively contributes to homeostasis. In the current review, we try to define a subtype of osteoarthritis (OA), metabolic OA, which is dependent on an unhealthy phenotype. METHODS: Peer-reviewed research articles and reviews were reviewed and summarized. Only literature readily available online, either by download or by purchase order, was included. RESULTS: OA is the most common joint disease and is more common in women after menopause. OA is a disease that affects the whole joint, including cartilage, subchondral bone, synovium, tendons, and muscles. The clinical endpoints of OA are pain and joint space narrowing, which is characterized by cartilage erosion and subchondral sclerosis, suggesting that cartilage is a central tissue of joint health. Thus, the joint, more specifically the cartilage, may be considered a target of endocrine function in addition to the well-described traditional risk factors of disease initiation and progression such as long-term loading of the joint due to obesity. Metabolic syndrome affects a range of tissues and may in part be molecularly described as a dysregulation of cytokines, adipokines, and hormones (e.g., estrogen and thyroid hormone). Consequently, metabolic imbalance may both directly and indirectly influence joint health and cartilage turnover, altering the progression of diseases such as OA. CONCLUSIONS: There is substantial evidence for a connection between metabolic health and development of OA. We propose that more focus be directed to understanding this connection to improve the management of menopausal health and associated comorbidities.


Assuntos
Cartilagem Articular/metabolismo , Hormônios/metabolismo , Menopausa/metabolismo , Osteoartrite/metabolismo , Distribuição da Gordura Corporal , Cartilagem Articular/patologia , Citocinas/metabolismo , Estrogênios/metabolismo , Feminino , Humanos , Articulações/metabolismo , Fenótipo , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo
18.
PLoS Genet ; 7(10): e1002310, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21998596

RESUMO

Seckel syndrome is a recessively inherited dwarfism disorder characterized by microcephaly and a unique head profile. Genetically, it constitutes a heterogeneous condition, with several loci mapped (SCKL1-5) but only three disease genes identified: the ATR, CENPJ, and CEP152 genes that control cellular responses to DNA damage. We previously mapped a Seckel syndrome locus to chromosome 18p11.31-q11.2 (SCKL2). Here, we report two mutations in the CtIP (RBBP8) gene within this locus that result in expression of C-terminally truncated forms of CtIP. We propose that these mutations are the molecular cause of the disease observed in the previously described SCKL2 family and in an additional unrelated family diagnosed with a similar form of congenital microcephaly termed Jawad syndrome. While an exonic frameshift mutation was found in the Jawad family, the SCKL2 family carries a splicing mutation that yields a dominant-negative form of CtIP. Further characterization of cell lines derived from the SCKL2 family revealed defective DNA damage induced formation of single-stranded DNA, a critical co-factor for ATR activation. Accordingly, SCKL2 cells present a lowered apoptopic threshold and hypersensitivity to DNA damage. Notably, over-expression of a comparable truncated CtIP variant in non-Seckel cells recapitulates SCKL2 cellular phenotypes in a dose-dependent manner. This work thus identifies CtIP as a disease gene for Seckel and Jawad syndromes and defines a new type of genetic disease mechanism in which a dominant negative mutation yields a recessively inherited disorder.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Nanismo/genética , Microcefalia/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Anormalidades Múltiplas/genética , Sequência de Aminoácidos , Proteínas Mutadas de Ataxia Telangiectasia , Sequência de Bases , Proteínas de Ciclo Celular/genética , Células Cultivadas , Dano ao DNA , DNA de Cadeia Simples , Nanismo/patologia , Mutação da Fase de Leitura , Genes Dominantes , Genes Recessivos , Instabilidade Genômica , Humanos , Microcefalia/patologia , Dados de Sequência Molecular , Proteínas Serina-Treonina Quinases/genética , Processamento de RNA/genética , Transdução de Sinais
19.
Arthritis Res Ther ; 13(2): 215, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21539724

RESUMO

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond.


Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/metabolismo , Biomarcadores/análise , Artrite Reumatoide/imunologia , Biomarcadores/metabolismo , Humanos
20.
Diabetes Metab Res Rev ; 27(4): 392-401, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21328517

RESUMO

BACKGROUND: Treatment of patients with perioxisome proliferator-activated receptor-γ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-γ agonists has not been established in a clinical trial. The BALaglitazone glucose Lowering Efficacy Trial aimed to establish the glucose-lowering effects and safety parameters of the perioxisome proliferator-activated receptor-γ partial agonist balaglitazone in diabetic patients on stable insulin therapy. METHODS: Four hundred and nine subjects from three countries with type 2 diabetes on stable insulin therapy were randomized to 26 weeks of double-blind treatment with once daily doses of 10 or 20 mg balaglitazone, 45 mg pioglitazone, or matching placebo (n ≥ 99 in each group). The primary endpoint was the efficacy of balaglitazone 10 and 20 mg versus placebo on the absolute change in haemoglobin A(1c) . Secondary endpoints included levels of fasting serum glucose, and changes in body composition and bone mineral density as measured by dual energy X-ray absorptiometry, in comparison to pioglitazone 45 mg. This study is registered with Clinicaltrials.gov identifier: NCT00515632. RESULTS: In the 10- and 20-mg balaglitazone groups, and in the 45-mg pioglitazone group, significant reductions in haemoglobin A(1c) levels were observed (−0.99, −1.11, and −1.22%, respectively; p < 0.0001) versus placebo. Fasting serum glucose was similarly reduced in all treatment arms. Dual energy X-ray absorptiometry analyses showed that, while balaglitazone at 10 mg caused weight gain and fluid retention compared to placebo, the magnitude of these effects was significantly smaller than that of pioglitazone 45 mg and balaglitazone 20mg. Balaglitazone at either dose did not appear to reduce bone mineral density, while Pioglitazone showed a trend towards a reduction. CONCLUSION: Patients treated with balaglitazone at 10 mg and 20 mg and pioglitazone at 45 mg showed clinically meaningful improvements in glucose levels and HbA(1c) . With the 10 mg dose, the benefits (glucose & HgA(1c) lowering) and untoward effects (fluid and fat accumulation) were less, results that encourage further studies of this drug candidate.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , PPAR gama/antagonistas & inibidores , Quinazolinas/uso terapêutico , Tiazolidinedionas/uso terapêutico , Idoso , Glicemia/análise , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pioglitazona , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
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