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1.
Proc Natl Acad Sci U S A ; 121(18): e2310283121, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38669183

RESUMO

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.


Assuntos
Proteínas de Transporte , Polaridade Celular , Proteínas de Membrana , Coluna Vertebral , Peixe-Zebra , Animais , Peixe-Zebra/genética , Peixe-Zebra/embriologia , Humanos , Camundongos , Polaridade Celular/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Coluna Vertebral/anormalidades , Coluna Vertebral/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Escoliose/genética , Escoliose/congênito , Escoliose/metabolismo , Via de Sinalização Wnt/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Feminino
2.
Gut ; 72(8): 1568-1580, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36450387

RESUMO

OBJECTIVE: Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB. DESIGN: We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models. RESULTS: We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1+ T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+ T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1+ T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models. CONCLUSION: Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Leucócitos Mononucleares , Terapia de Imunossupressão , Tolerância Imunológica , Imunoterapia , Nivolumabe/uso terapêutico , Linfócitos T CD8-Positivos
3.
Brain ; 144(9): 2759-2770, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34428276

RESUMO

The molecular link between amyloid-ß plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer's disease, is still unclear. Increasing evidence suggests that amyloid-ß peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-ß-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer's disease and in APP transgenic mice, and plays a key role between amyloid-ß and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-ß peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-ß toxicity pathway. Mechanistically, amyloid-ß upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3ß, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3ß activation and tau pathology, providing novel potential targets for pharmaceutical intervention.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , Fator de Transcrição PAX6/metabolismo , Fragmentos de Peptídeos/toxicidade , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
4.
Psychogeriatrics ; 22(1): 84-98, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34729865

RESUMO

BACKGROUND: Mild behavioural impairment (MBI) is a neurobehavioural syndrome characterised by later life emergence of persistent neuropsychiatric symptoms. Our previous meta-analysis showed that MBI is prevalent among cognitively normal (CN), subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) subjects. This study is to calculate the pooled prevalence of MBI domains among CN, SCI, and MCI subjects. METHODS: A search of relevant literature published between 1 January 2003 and 6 August 2021 was conducted. Meta-analysis using a random effects model and meta-regression was performed. RESULTS: Ten studies conducted among 12 067 subjects (9758 CN, 1057 SCI and 1252 MCI) with retrievable MBI domains data underwent meta-analysis, revealing pooled prevalence of affective dysregulation (AFD), impulse dyscontrol (IDS), decreased motivation (DMT), social inappropriateness (SIP) and abnormal perception/thought (APT) of 32.84% (95% CI 24.44-42.5%), 26.67% (95% CI 18.24-37.23%), 12.58% (95% CI 6.93-21.75%), 6.05% (95% CI 3.44-10.42%), and 2.81% (95% CI 1.67-4.69%) respectively. AFD and APT domains demonstrated ordinal increase in pooled prevalence from CN, SCI and MCI subgroups, but meta-regression demonstrated no significant difference in MBI domains prevalence among cognitive subgroups (in contrast to the significant increase in MBI prevalence from CN to SCI to MCI). The pooled prevalence of AFD and IDS are greater than that of DMT, SIP and APT among all cognitive subgroups. Several variables were found to explain the high heterogeneity. CONCLUSIONS: AFD and IDS are the two most prevalent MBI domains and remain the same with cognitive deterioration. This finding is potentially relevant to clinical practice.


Assuntos
Transtornos Cognitivos , Disfunção Cognitiva , Disfunção Cognitiva/epidemiologia , Humanos , Prevalência
5.
Eur J Neurosci ; 54(4): 5310-5326, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34309092

RESUMO

The glutamatergic cycle is essential in modulating memory processing by the hippocampal circuitry. Our combined proton magnetic resonance spectroscopy (1 H-MRS) and task-based functional magnetic resonance imaging (fMRI) study (using face-name paired-associates encoding and retrieval task) of a cognitively normal cohort of 67 healthy adults (18 ApoE4 carriers and 49 non-ApoE4 carriers) found altered patterns of relationships between glutamatergic-modulated synaptic signalling and neuronal activity or functional hyperaemia in the ApoE4 isoforms. Our study highlighted the asymmetric left-right hippocampal glutamatergic system in modulating neuronal activities in ApoE4 carriers versus non-carriers. Such brain differentiation might be developmental cognitive advantages or compensatory due to impaired synaptic integrity and plasticity in ApoE4 carriers. As there was no difference in myoinositol levels measured by MRS between the ApoE4 and non-ApoE4 subgroups, the mechanism is unlikely to be a response to neuroinflammation.


Assuntos
Doença de Alzheimer , Hipocampo , Adulto , Apolipoproteína E4/genética , Encéfalo , Cognição , Humanos , Imageamento por Ressonância Magnética
6.
J Magn Reson Imaging ; 54(3): 952-961, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33939228

RESUMO

BACKGROUND: Apolipoprotein E ɛ4 allele (ApoE4) is the most common gene polymorphism related to Alzheimer's disease (AD). Impaired synaptic dysfunction occurs in ApoE4 carriers before any clinical symptoms. It remains unknown whether ApoE4 status affects the hippocampal neuromodulation, which further influences brain network topology. PURPOSE: To study the relationship of regional and global network properties by using graph theory analysis and glutamatergic (Glx) neuromodulation in the ApoE isoforms. STUDY TYPE: Prospective. SUBJECTS: Eighty-four cognitively normal adults (26 ApoE4 and 58 non-ApoE4 carriers). FIELD STRENGTH/SEQUENCE: Gradient-echo echo-planar and point resolved spectroscopy sequence at 3 T. ASSESSMENT: Glx concentration in bilateral hippocampi were processed with jMRUI (4.0), and graph theory metrics (global: γ, λ, small-worldness in whole brain; regional: nodal clustering coefficient (Ci ) and nodal characteristic path length (Li )) in top 20% highly connected hubs of subgroups (low-risk: non-ApoE4; high-risk: APOE4) were calculated and compared. STATISTICAL TESTS: Two-sample t test was used to compare metrics between subgroups. Correlations between regional properties and Glx by Pearson's partial correlation with false discovery rate correction. RESULTS: Significant differences (P < 0.05) in Ci between subgroups were found in hubs of left inferior frontal, bilateral inferior temporal, and bilateral precentral gyri, right parahippocampus, and bilateral precuneus. In addition, there was a significant correlation between Glx in the left hippocampus and Ci in inferior frontal gyrus (r = -0.537, P = 0.024), right inferior temporal (r = -0.478, P = 0.043), right parahippocampus (r = -0.629, P = 0.016), left precentral (r = -0.581, P = 0.022), right precentral (r = -0.651, P = 0.003), left precuneus (r = -0.545, P = 0.024), and right precuneus (r = -0.567, P = 0.022); and Li in left precuneus (r = 0.575, P = 0.032) and right precuneus (r = 0.586, P = 0.032) in the high-risk group, but not in the low-risk group. DATA CONCLUSION: Our results suggested that healthy ApoE4 carriers exhibit poorer local interconnectivity. Moreover, the close relationship between glutamate and small-world network properties in ApoE4 carriers might reflect a compensatory response to the impaired network efficiency. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.


Assuntos
Doença de Alzheimer , Glutamina , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Encéfalo , Ácido Glutâmico , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Estudos Prospectivos
7.
Nucleic Acids Res ; 47(4): 1628-1636, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30590725

RESUMO

Bound by transcription factors, DNA motifs (i.e. transcription factor binding sites) are prevalent and important for gene regulation in different tissues at different developmental stages of eukaryotes. Although considerable efforts have been made on elucidating monomeric DNA motif patterns, our knowledge on heterodimeric DNA motifs are still far from complete. Therefore, we propose to develop a computational approach to synthesize a heterodimeric DNA motif from two monomeric DNA motifs. The approach is sequentially divided into two components (Phases A and B). In Phase A, we propose to develop the inference models on how two DNA monomeric motifs can be oriented and overlapped with each other at nucleotide level. In Phase B, given the two monomeric DNA motifs oriented, we further propose to develop DNA-binding family-specific input-output hidden Markov models (IOHMMs) to synthesize a heterodimeric DNA motif. To validate the approach, we execute and cross-validate it with the experimentally verified 618 heterodimeric DNA motifs across 49 DNA-binding family combinations. We observe that our approach can even "rescue" the existing heterodimeric DNA motif pattern (i.e. HOXB2_EOMES) previously published on Nature. Lastly, we apply the proposed approach to infer previously uncharacterized heterodimeric motifs. Their motif instances are supported by DNase accessibility, gene ontology, protein-protein interactions, in vivo ChIP-seq peaks, and even structural data from PDB. A public web-server is built for open accessibility and scientific impact. Its address is listed as follows: http://motif.cs.cityu.edu.hk/custom/MotifKirin.


Assuntos
Biologia Computacional , Genômica/métodos , Motivos de Nucleotídeos/genética , Fatores de Transcrição/genética , Algoritmos , Sítios de Ligação/genética , Replicação do DNA/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Cadeias de Markov , Elementos Reguladores de Transcrição/genética , Análise de Sequência de DNA/métodos , Software , Fatores de Transcrição/química
8.
BMC Musculoskelet Disord ; 22(1): 72, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435951

RESUMO

BACKGROUND: There is no recommended standard for positioning of a mouse for radiographic assessment of the spine. This is necessary to have reproducible radiographic data and avoid false positive results. The objective of this study was to investigate the impact of various postures on Cobb angle measurements and to set up a positioning standard for imaging mouse spines. METHODS: This study was conducted in three parts. Firstly, we identified the problem of lack of posture standardization for radiographs. We collected 77 C57BL/6 J mice for spine radiographs and found a scoliosis prevalence of 28.6% with large variations in curve magnitude. Secondly, 24 C57BL/6 J mice underwent 4 consecutive weekly radiographs and observed high variations (relative standard deviation: 125.3%) between radiographs. Thirdly, we collected another 82 C57BL/6 J mice and designed 14 different postures that could take place during imaging. These postures were related to curling of the limbs, and head, pelvic and tail tilting. RESULTS: The results showed that head and pelvic tilting significantly affects the curve magnitude with effect size (Glass's delta) over 1.50. Avoiding these incorrect positions during radiographs is warranted. The standard recommended posture for mouse imaging entails positioning the snout, interorbital space, neck and whole spine in one line, and with the limbs placed symmetrical to the trunk, whilst avoiding stretching the body of the mouse. CONCLUSIONS: Our work exemplified the importance of standard protocol during imaging when using an animal model in the scoliosis study. We recommend utilizing this standard in studying various disorders of the spine to avoid technical causes for the appearance of a curve.


Assuntos
Escoliose , Animais , Extremidades , Camundongos , Camundongos Endogâmicos C57BL , Postura , Radiografia , Escoliose/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem
9.
Molecules ; 26(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064330

RESUMO

Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for Alzheimer's disease (AD). However, findings on the effects of TREM2 on Aß deposition are quite inconsistent in animal studies, requiring further investigation. In this study, we investigated whether elevation of TREM2 mitigates Aß pathology in TgCRND8 mice. We found that peripheral nerve injury resulted in a robust elevation of TREM2 exclusively in reactive microglia in the ipsilateral spinal cord of aged TgCRND8 mice at the age of 20 months. TREM2 expression appeared on day 1 post-injury and the upregulation was maintained for at least 28 days. Compared to the contralateral side, neither amyloid beta plaque load nor soluble Aß40 and Aß42 levels were attenuated upon TREM2 induction. We further showed direct evidence that TREM2 elevation in reactive microglia did not affect amyloid-ß pathology in plaque-bearing TgCRND8 mice by applying anti-TREM2 neutralizing antibody to selectively block TREM2. Our results question the ability of TREM2 to ameliorate established Aß pathology, discouraging future development of disease-modifying pharmacological treatments targeting TREM2 in the late stage of AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Microglia/patologia , Receptores Imunológicos/metabolismo , Envelhecimento/patologia , Animais , Plexo Braquial , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Nervos Periféricos/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Corno Dorsal da Medula Espinal/patologia
10.
Psychogeriatrics ; 21(1): 100-111, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33260271

RESUMO

AIM: Mild behavioural impairment (MBI) is a neurobehavioural syndrome characterized by emergent neuropsychiatric symptoms in later life. There has been no systematic review or meta-analysis on the prevalence of MBI. The main aim of the study is to calculate the pooled prevalence of MBI. METHODS: A search of the literature on MBI in mild cognitive impairment (MCI), cognitively normal (CN), and subjective cognitive impairment (SCI) and CN but at risk (CN-AR) subjects published between 1 January 2003 and 28 September 2020 was conducted. Meta-analysis using a random effects model was performed to determine the pooled estimate of the prevalence of MBI. Meta-regression was performed to identify factors contributing to the variance of prevalence rate. A systematic review was also performed to study the impact of MBI in cognitive outcomes and its correlation to the pathology and genetics of Alzheimer's disease. RESULTS: Eleven studies conducted among 15 689 subjects underwent meta-analysis, revealing the pooled prevalence of MBI to be 33.5% (95% confidence interval (CI): 22.6%-46.6%). Seven studies conducted among 1358 MCI subjects underwent meta-analysis, revealing the pooled prevalence to be 45.5% (95%CI: 36.1%-55.3%). Four studies conducted among 13 153 CN subjects underwent meta-analysis, revealing the pooled prevalence to be 17.0% (95%CI: 7.2%-34.9%). Five studies conducted among 1158 SCI or CN-AR subjects underwent meta-analysis, revealing the pooled prevalence to be 35.8% (95%CI: 21.4%-53.2%). A systematic review of 13 studies showed that MBI has a significant impact on cognitive deterioration and is associated with the pathology and genetics of Alzheimer's disease. CONCLUSIONS: In MCI, CN, and SCI and CN-AR subjects, MBI is common. Our finding is potentially useful in planning future clinical trials.


Assuntos
Doença de Alzheimer , Transtornos Cognitivos , Disfunção Cognitiva , Doença de Alzheimer/epidemiologia , Disfunção Cognitiva/epidemiologia , Progressão da Doença , Humanos , Prevalência
11.
Hum Mol Genet ; 27(22): 3986-3998, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30395268

RESUMO

Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value_rs4513093 = 1.7E-15), ABO (P-value_ rs687621 = 7.3E-10) and SOX6 (P-value_rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Caderinas/genética , Doenças Musculoesqueléticas/genética , Fatores de Transcrição SOXD/genética , Escoliose/genética , Adolescente , Criança , Etnicidade/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Doenças Musculoesqueléticas/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Escoliose/fisiopatologia , Adulto Jovem
12.
Brain Behav Immun ; 89: 628-640, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32739364

RESUMO

Beta amyloid (Aß) is a key component of parenchymal Aß plaques and vascular Aß fibrils, which lead to cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). Recent studies have revealed that Aß contained in the cerebrospinal fluid (CSF) can re-enter into brain through paravascular spaces. However, whether Aß in CSF may act as a constant source of pathogenic Aß in AD is still unclear. This study aimed to examine whether Aß pathology could be worsened when CSF Aß level was enhanced by intra-cisternal infusion of aged brain extract containing abundant Aß in TgCRND8 host mice. TgCRND8 mouse is an AD animal model which develops predominant parenchymal Aß plaques in the brain at as early as 3 months of age. Here, we showed that single intracisternal injection of Aß seeds into TgCRND8 mice before the presence of Aß pathology induced robust prion-like propagation of CAA within 90 days. The induced CAA is mainly distributed in the cerebral cortex, hippocampus and thalamus of TgCRND8 mice. Surprisingly, despite the robust increase in CAA levels, the TgCRND8 mice had a marked decrease in parenchymal Aß plaques and the plaques related neuroinflammation in the brains compared with the control mice. These results amply indicate that Aß in CSF may act as a source of Aß contributing to the growth of vascular Aß deposits in CAA. Our findings provide experimental evidence to unravel the mechanisms of CAA formation and the potential of targeting CSF Aß for CAA.


Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Placa Amiloide
13.
J Hum Genet ; 64(5): 493-498, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30787423

RESUMO

Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis. Controlling its curve progression is the most important clinical task. Although recent genome-wide association studies (GWASs) identified several susceptibility loci associated with the development of AIS, the etiology of curve progression has been still unknown. Our previous GWAS has identified that rs12946942 showed significant association with severe AIS. To confirm the association, we conducted an international meta-analysis using four cohorts with different ethnicity. We analyzed 2272 severe AIS cases and 13,859 controls in total, and found the replication of significant association of rs12946942 (combined P = 7.23×10-13; odds ratio = 1.36, 95% confidence interval = 1.25-1.49). In silico analyses suggested that SOX9 is the most likely susceptibility gene for AIS curve progression in the locus.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo Genético , Fatores de Transcrição SOX9/genética , Escoliose/etnologia , Escoliose/genética , Adolescente , Feminino , Humanos , Masculino
14.
Funct Integr Genomics ; 18(4): 411-424, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29564647

RESUMO

Host genetic factors play an important role in diverse host outcomes after influenza A (H7N9) infection. Studying differential responses of inbred mouse lines with distinct genetic backgrounds to influenza virus infection could substantially increase our understanding of the contributory roles of host genetic factors to disease severity. Here, we utilized an integrated approach of mRNA-seq and miRNA-seq to investigate the transcriptome expression and regulation of host genes in C57BL/6J and DBA/2J mouse strains during influenza virus infection. The differential pathogenicity of influenza virus in C57BL/6J and DBA/2J has been fully demonstrated through immunohistochemical staining, histopathological analyses, and viral replication assessment. A transcriptional molecular signature correlates to differential host response to infection has been uncovered. With the introduction of temporal expression pattern analysis, we demonstrated that host factors responsible for influenza virus replication and host-virus interaction were significantly enriched in genes exhibiting distinct temporal dynamics between different inbred mouse lines. A combination of time-series expression analysis and temporal expression pattern analysis has provided a list of promising candidate genes for future studies. An integrated miRNA regulatory network from both mRNA-seq and miRNA-seq revealed several regulatory modules responsible for regulating host susceptibilities and disease severity. Overall, a comprehensive framework for analyzing host susceptibilities to influenza infection was established by integrating mRNA-seq and miRNA-seq data of inbred mouse lines. This work suggests novel putative molecular targets for therapeutic interventions in seasonal and pandemic influenza.


Assuntos
Predisposição Genética para Doença , MicroRNAs/genética , Infecções por Orthomyxoviridae/genética , RNA Mensageiro/genética , Animais , Interações Hospedeiro-Patógeno , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Infecções por Orthomyxoviridae/virologia
15.
Hum Genet ; 137(6-7): 553-567, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30019117

RESUMO

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.


Assuntos
Anormalidades Congênitas/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Escoliose/genética , Adolescente , Anormalidades Congênitas/fisiopatologia , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Haplótipos/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Escoliose/fisiopatologia
16.
BMC Bioinformatics ; 18(1): 90, 2017 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-28166716

RESUMO

BACKGROUND: Recently, several tools have been designed for human leukocyte antigen (HLA) typing using single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) data. These tools provide high-throughput and cost-effective approaches for identifying HLA types. Therefore, tools for downstream association analysis are highly desirable. Although several tools have been designed for multi-allelic marker association analysis, they were designed only for microsatellite markers and do not scale well with increasing data volumes, or they were designed for large-scale data but provided a limited number of tests. RESULTS: We have developed a Python package called PyHLA, which implements several methods for HLA association analysis, to fill the gap. PyHLA is a tailor-made, easy to use, and flexible tool designed specifically for the association analysis of the HLA types imputed from genome-wide genotyping and NGS data. PyHLA provides functions for association analysis, zygosity tests, and interaction tests between HLA alleles and diseases. Monte Carlo permutation and several methods for multiple testing corrections have also been implemented. CONCLUSIONS: PyHLA provides a convenient and powerful tool for HLA analysis. Existing methods have been integrated and desired methods have been added in PyHLA. Furthermore, PyHLA is applicable to small and large sample sizes and can finish the analysis in a timely manner on a personal computer with different platforms. PyHLA is implemented in Python. PyHLA is a free, open source software distributed under the GPLv2 license. The source code, tutorial, and examples are available at https://github.com/felixfan/PyHLA.


Assuntos
Alelos , Biologia Computacional/métodos , Antígenos HLA/genética , Software , Genoma Humano , Técnicas de Genotipagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Lineares , Modelos Logísticos , Repetições de Microssatélites , Modelos Teóricos , Polimorfismo de Nucleotídeo Único
17.
J Formos Med Assoc ; 115(2): 67-75, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26337232

RESUMO

There are great diversities of clinical phenotypes among the various familial Alzheimer's disease (FAD) families. We aimed to systematically review all the previously reported cases of FAD and to perform comparisons between Asian and white patients. In this regard, we collected individual-level data from 658 pedigrees. We found that patients with presenilin 1 (PSEN1) mutations had the earliest age of onset (AOO; 43.3 ± 8.6 years, p < 0.001) and were more commonly affected by seizures, spastic paraparesis, myoclonus, and cerebellar signs (p < 0.001, p < 0.001, p = 0.003, and p = 0.002, respectively). Patients with PSEN2 mutations have a delayed AOO with longest disease duration and presented more frequently with disorientation (p = 0.03). Patients with amyloid precursor protein (APP) mutations presented more frequently with aggression (p = 0.02) and those with APP duplication presented more frequently with apraxia (p = 0.03). PSEN1 mutations before codon 200 had an earlier AOO than those having mutations after codon 200 (41.4 ± 8.0 years vs. 44.7 ± 8.7 years, p < 0.001). Because 42.9% of the mutations reported are novel, the mutation spectrum and clinical features in Asian FAD families could be different from that of whites. Asian patients with PSEN1 mutations presented more frequently with disorientation (p = 0.02) and personality change (p = 0.01) but less frequently with atypical clinical features. Asian patients with APP mutations presented less frequently with aphasia (p = 0.02). Thus, clinical features could be modified by underlying mutations, and Asian FAD patients may have different clinical features when compared with whites.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Presenilina-2/genética , Doença de Alzheimer/etnologia , Povo Asiático , Humanos , Mutação , Linhagem , Taiwan
18.
Nat Genet ; 39(2): 168-77, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17220890

RESUMO

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.


Assuntos
Doença de Alzheimer/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Idade de Início , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Linhagem Celular , Endossomos/metabolismo , Variação Genética , Haplótipos , Humanos , Íntrons , Modelos Genéticos , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Nexinas de Proteases , Receptores de Superfície Celular/metabolismo , Proteínas de Transporte Vesicular/metabolismo
19.
J Infect Dis ; 212(8): 1214-21, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25904605

RESUMO

The genetic predisposition to severe A(H1N1)2009 (A[H1N1]pdm09) influenza was evaluated in 409 patients, including 162 cases with severe infection and 247 controls with mild infection. We prioritized candidate variants based on the result of a pilot genome-wide association study and a lung expression quantitative trait locus data set. The GG genotype of rs2070788, a higher-expression variant of TMPRSS2, was a risk variant (odds ratio, 2.11; 95% confidence interval, 1.18-3.77; P = .01) to severe A(H1N1)pdm09 influenza. A potentially functional single-nucleotide polymorphism, rs383510, accommodated in a putative regulatory region was identified to tag rs2070788. Luciferase assay results showed the putative regulatory region was a functional element, in which rs383510 regulated TMPRSS2 expression in a genotype-specific manner. Notably, rs2070788 and rs383510 were significantly associated with the susceptibility to A(H7N9) influenza in 102 patients with A(H7N9) influenza and 106 healthy controls. Therefore, we demonstrate that genetic variants with higher TMPRSS2 expression confer higher risk to severe A(H1N1)pdm09 influenza. The same variants also increase susceptibility to human A(H7N9) influenza.


Assuntos
Vírus da Influenza A Subtipo H1N1/genética , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/virologia , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Índice de Gravidade de Doença
20.
J Med Genet ; 51(6): 401-6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24721834

RESUMO

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). METHODS: Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. RESULTS: We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. CONCLUSIONS: Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.


Assuntos
Povo Asiático/genética , Proteínas de Homeodomínio/genética , Escoliose/genética , Fatores de Transcrição/genética , Adolescente , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único
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