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1.
Parkinsonism Relat Disord ; 124: 106989, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38754220

RESUMO

The ATP10B gene has been proposed to play an important role in the development of early-onset Parkinson's disease (PD). Nevertheless, various studies have presented controversial conclusions regarding the involvement of this gene in PD. Here, we screened 1162 patients with PD, employing a targeted resequencing approach to investigate the putative relevance of this gene in a large independent cohort of these patients from southern Spain. Variations were classified according to the American College of Medical Genetics and Genomics criteria. Association studies were performed using data of a representative healthy Spanish population from the Medical Genome Project. Frequent variants were excluded. A total of 68 variants (rare or very rare) were detected in our cohort. Among ATP10B variant carriers, 12.9 % were putative compound heterozygous carriers; of these, 25 % were patients with early-onset PD. No evidence of a relation between any rare variants of ATP10B and PD risk was observed. Therefore, our results do not support a role for ATP10B in the onset of PD, or in the risk of developing it.


Assuntos
Doença de Parkinson , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Coortes , Predisposição Genética para Doença , Doença de Parkinson/genética , Espanha/epidemiologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo
2.
NPJ Parkinsons Dis ; 9(1): 12, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36720879

RESUMO

Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson's Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.

3.
J Thromb Haemost ; 20(6): 1331-1349, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35285134

RESUMO

BACKGROUND: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. OBJECTIVES: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. METHODS: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). RESULTS: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. CONCLUSIONS: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.


Assuntos
Doenças Cardiovasculares , Hemostáticos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Fator XI/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hemostasia/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Ativador de Plasminogênio Tecidual/genética
4.
Nat Commun ; 12(1): 3098, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035282

RESUMO

The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Vasos Sanguíneos/metabolismo , Encéfalo/metabolismo , Neovascularização Patológica/genética , Placa Amiloide/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Vasos Sanguíneos/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Placa Amiloide/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
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