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1.
Front Pediatr ; 10: 771374, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35356445

RESUMO

Type 50 early infantile epileptic encephalopathy, or EIEE-50 for short, is an autosomal recessive genetic disorder resulting from CAD mutations. So far, little has been reported on the disease. In this article, we will discuss the case of a male infant who is 8 years and 5 months old. A whole-exome sequencing of the boy revealed CAD compound heterozygous mutations. He suffered from global developmental delay and regression, refractory epilepsy, and anemia. After his diagnosis, we used uridine treatment and gained encouraging results. In this article, we will analyze our case studies in the context of the literature, so as to improve pediatricians' understanding of the disease.

2.
Mol Med Rep ; 25(3)2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35088893

RESUMO

Subsequently to the publication of this paper, while performing a careful re­examination of the scientific integrity of the data included in their publications, the authors have realized that they inadvertently used the incorrect western blotting images in Fig. 2B of this article, However, still having access to their original data, the authors were able to reassemble Fig. 2 correctly, and the corrected version of this figure is shown below. Note that this error did not significantly affect the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors thank the Editor of Molecular Medicine Reports for granting them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published on Molecular Medicine Reports 14: 1709­1713, 2016; DOI: 10.3892/mmr.2016.5411].

3.
J Parkinsons Dis ; 12(1): 27-44, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34719435

RESUMO

Parkinson's disease is a debilitating neurodegenerative disorder whose etiology is still unclear, hampering the development of effective treatments. There is an urgent need to identify the etiology and provide further effective treatments. Recently, accumulating evidence has indicated that infection may play a role in the etiology of Parkinson's disease. The infective pathogens may act as a trigger for Parkinson's disease, the most common of which are hepatitis C virus, influenza virus, and Helicobacter pylori. In addition, gut microbiota is increasingly recognized to influence brain function through the gut-brain axis, showing an important role in the pathogenesis of Parkinson's disease. Furthermore, a series of anti-infective agents exhibit surprising neuroprotective effects via various mechanisms, such as interfering with α-synuclein aggregation, inhibiting neuroinflammation, attenuating oxidative stress, and preventing from cell death, independent of their antimicrobial effects. The pleiotropic agents affect important events in the pathogenesis of Parkinson's disease. Moreover, most of them are less toxic, clinically safe and have good blood-brain penetrability, making them hopeful candidates for the treatment of Parkinson's disease. However, the use of antibiotics and subsequent gut dysbiosis may also play a role in Parkinson's disease, making the long-term effects of anti-infective drugs worthy of further consideration and exploration. This review summarizes the current evidence for the association between infective pathogens and Parkinson's disease and subsequently explores the application prospects of anti-infective drugs in Parkinson's disease treatment, providing novel insights into the pathogenesis and treatment of Parkinson's disease.


Assuntos
Microbioma Gastrointestinal , Doenças Neurodegenerativas , Doença de Parkinson , Antibacterianos/uso terapêutico , Disbiose/tratamento farmacológico , Disbiose/metabolismo , Microbioma Gastrointestinal/fisiologia , Humanos , Doença de Parkinson/terapia
4.
Acta Neurol Scand ; 145(4): 434-441, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34927233

RESUMO

BACKGROUND: The factors associated with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis relapse are yet to be elucidated. AIMS OF THE STUDY: To investigate the factors associated with relapse and prognosis of anti-NMDA receptor encephalitis. METHODS: This retrospective study included patients diagnosed with anti-NMDA receptor encephalitis admitted to the First Affiliated Hospital of Zhengzhou University from January 2013 to October 2019. The clinical features, auxiliary examinations, treatment regimens, and follow-up were recorded. The outcomes were relapse and 2-year disease prognosis. RESULTS: A total of 160 patients were included. Consequently, 6 (5%) deaths, 34 (25.4%) relapses, and 19 (15.2%) patients had a poor prognosis (modified Rankin score (mRS) ≥3) were recorded. The multivariable analyses showed that age (p = .011), abnormal magnetic resonance imaging (MRI) (p = .019), glucocorticoid pulse (p = .009), and intracranial pressure (p = .023) were independently associated with the relapse, while age (p = .030) and central hypoventilation (p = .020) were independently associated with a poor prognosis at 2 years. CONCLUSION: Glucocorticoid pulse therapy reduces the relapse of anti-NMDA receptor encephalitis. Age, abnormal MRI, and intracranial pressure are risk factors for relapse, while age and central hypoventilation are independently associated with poor prognosis.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico por imagem , Pré-Escolar , Humanos , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/complicações , Receptores de N-Metil-D-Aspartato , Estudos Retrospectivos
6.
Front Genet ; 12: 679363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34168680

RESUMO

BACKGROUND AND OBJECTIVE: Evidence suggests that interleukin-6 (IL6) signaling is causally associated with aortic aneurysm independently of the effect of C-reactive protein (CRP). We aimed to explore the genetic overlap and associations between inflammation (IL6 signaling and CRP) and intracranial aneurysm (IA) risk. METHODS: Two-sample Mendelian randomization (MR) methods were used to assess the causal effects of soluble IL6 receptor (sIL6R) (n = 21,758) and CRP (n = 204,402) levels on IA (7,495 cases and 71,934 controls) risk using genome-wide association study summary data of European individuals. Cross-trait linkage disequilibrium score regression was used to estimate the genetic correlations of CRP (n = 400,094) with IA. RESULTS: MR analyses showed that circulating sIL6R and CRP levels were not associated with the risk of IA. The odds ratios based on the inverse variance-weighted method were 0.986 (0.950-1.023, p = 0.45) and 0.957 (0.846-1.084, p = 0.49) for sIL6R and CRP, respectively. MR analyses using data of ruptured and unruptured IA each showed no association. Linkage disequilibrium score regression showed that the genetic correlation between CRP and IA was 0.16 (SE = 0.04, p = 0.0003). The genetic correlation diminished after conditioning IA on blood pressure (0.07 ± 0.05, p = 0.16), smoking (0.02 ± 0.05, p = 0.65), or blood pressure plus smoking (-0.03 ± 0.05, p = 0.53). CONCLUSION: Using associated genetic variants as instrument variables, two-sample MR analyses showed no evidence that circulating sIL6R and CRP levels were associated with IA risk. Although a positive genetic correlation was found between CRP levels and IA risk, it was mainly driven by the shared genetic background of blood pressure and smoking with both CRP and IA.

7.
Parkinsons Dis ; 2021: 8891874, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007439

RESUMO

This meta-analysis aimed to evaluate the accuracy of hyperechogenicity of the substantia nigra (SN) for the differential diagnosis of Parkinson's disease (PD) and other movement disorders. We systematically searched the PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure databases for relevant studies published between January 2015 and May 2020. Eligible articles comparing the echogenicity of the SN between patients with PD and those with other movement disorders were screened, and two independent reviewers extracted data according to the inclusion and exclusion criteria. Statistical analyses were conducted using STATA (version 15.0) (Stata Corporation, College Station, TX, USA), Review Manager 5.3 (Cochrane Collaboration), and Meta-DiSc1.4 to assess the pooled diagnostic value of transcranial sonography (TCS) for PD. Nine studies with a total of 1046 participants, including 669 patients with PD, were included in the final meta-analysis. Our meta-analysis demonstrated that hyperechogenicity of the SN had a pooled sensitivity and specificity of 0.85 (0.82, 0.87) and 0.71 (0.66, 0.75), respectively, for distinguishing idiopathic Parkinson's disease from other movement disorders. Furthermore, the area under the curve of the summary receiver operating characteristic was 0.94. Transcranial sonography of the SN is a valuable tool for the differential diagnosis of PD and other movement disorders.

8.
Biomed Res Int ; 2021: 6631856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791368

RESUMO

Oral submucous fibrosis (OSMF) is a kind of chronic, insidious disease, and it is categorized into potentially malignant disorders (PMD), which poses a global and regional problem to public health. It is considered to be a multifactorial disease, such as due to areca nut chewing, trace element disorders, and genetic susceptibility. However, there is still no unanimous conclusion on its pathogenesis, diagnosis, and treatment strategies. Hence, this article provides a comprehensive review and prospect of OSMF research, providing scholars and clinicians with a better perspective and new ideas for the research and treatment of OSMF.


Assuntos
Areca/efeitos adversos , Neoplasias Bucais , Fibrose Oral Submucosa , Humanos , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fibrose Oral Submucosa/induzido quimicamente , Fibrose Oral Submucosa/metabolismo , Fibrose Oral Submucosa/patologia
9.
Stem Cell Res ; 52: 102257, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33626493

RESUMO

Here, we describe the generation of an induced pluripotent stem cell (iPSC) line, from a female patient diagnosed with Parkinson's disease (PD). The patient carries a heterozygous intermediate-length GGC repeat expansions mutation in the NOTCH2NLC gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver Klf4, OCT3/4, SOX2 and c-MYC factors. The generated iPSC line (ZZUi020-A) presented with expression of common pluripotency markers, showed potential of differentiating into derivatives of the three germ layers, and displayed a normal karyotype. The clone ZZUi020-A is presented thereafter, it can be used to study the mechanisms underlying NOTCH2NLC-PD pathogenesis.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , Diferenciação Celular , Células Cultivadas , Feminino , Camadas Germinativas , Heterozigoto , Humanos , Mutação , Doença de Parkinson/genética
10.
Int J Stroke ; 16(3): 265-272, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32223541

RESUMO

In China, stroke is a major cause of mortality, and long-term physical and cognitive impairment. To meet this challenge, the Ministry of Health China Stroke Prevention Project Committee (CSPPC) was established in April 2011. This committee actively promotes stroke prevention and control in China. With government financial support of 838.4 million CNY, 8.352 million people from 536 screening points in 31 provinces have received stroke screening and follow-up over the last seven years (2012-2018). In 2016, the CSPPC issued a plan to establish stroke centers. To shorten the pre-hospital period, the CSPPC established a stroke center network, stroke map, and stroke "Green Channel" to create three 1-h gold rescue circles, abbreviated as "1-1-1" (onset to call time <1 h; pre-hospital transfer time < 1 h, and door-to-needle time < 1 h). From 2017 to 2018, the median door-to-needle time dropped by 4.0% (95% confidence interval (CI), 1.4-9.4) from 50 min to 48 min, and the median onset-to-needle time dropped by 2.8% (95% CI, 0.4-5.2) from 180 min to 175 min. As of 31 December 2018, the CSPPC has established 380 stroke centers in mainland China. From 1 November 2018, the CSPPC has monitored the quality of stroke care in stroke center hospitals through the China Stroke Data Center Data Reporting Platform. The CSPPC Stroke program has led to a significant improvement in stroke care. This program needs to be further promoted nationwide.


Assuntos
Acidente Vascular Cerebral , China/epidemiologia , Hospitais , Humanos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Terapia Trombolítica , Tempo para o Tratamento
11.
Ann Neurol ; 89(1): 182-187, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33016348

RESUMO

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182-187.


Assuntos
Doenças Neurodegenerativas/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Adulto , Idoso , Biópsia , Encéfalo/patologia , Estudos de Coortes , Feminino , Humanos , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Linhagem , Receptor Notch2/metabolismo
13.
Sci Rep ; 10(1): 19132, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154471

RESUMO

Dual antiplatelet therapy (DAPT) reduced stroke risk in high-risk transient ischemic attack (TIA) patients assessed by ABCD2 score. Patients with positive diffusion-weighted imaging (DWI) were identified as imaging-based high-risk. The present study aims to investigate whether DAPT could reduce stroke risk in TIA with DWI positive. The study enrolled TIA patients within 72 h of onset from the prospective TIA database of the First Affiliated Hospital of Zhengzhou University. The predictive outcome was ischemic stroke at 90-day. The relationship between DAPT and stroke was analyzed in a cox proportional hazards model. The Kaplan-Meier curves of TIA patients with DAPT and monotherapy were plotted. Total of 661 TIA patients were enrolled, 279 of whom were DWI positive and 281 used DAPT. The 90-day stroke risk was higher in patients used monotherapy than those used DAPT in TIA with positive DWI (23.7% vs. 13.4%, p = 0.029). DAPT was associated with reduced stroke risk in TIA patients with positive DWI (hazard ratio [HR] = 0.54; 95% confidence interval [CI], 0.30-0.97; p = 0.037). However, the benefit didn't exist in TIA patients with negative DWI (HR = 0.43; 95% CI, 0.14-1.33; p = 0.142). Early use of DAPT reduced stroke risk in TIA patients with positive DWI.


Assuntos
Aspirina/uso terapêutico , Encéfalo/diagnóstico por imagem , Clopidogrel/uso terapêutico , Ataque Isquêmico Transitório/complicações , AVC Isquêmico/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Adulto , Idoso , Imagem de Difusão por Ressonância Magnética , Quimioterapia Combinada , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico por imagem , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
14.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 235-239, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981278

RESUMO

Objective: To investigate the effects of exogenous NaHS on myelin basic protein (MBP) and learning and memory of hippocampal neurons in mice with spinocerebellar ataxia type 3 (SCA3) and its therapeutic significance.Methods: Twelve male normal mice were randomly selected as normal control group (NC Group), and 48 SCA3 mice were randomly selected as SCA3 model group (M Group), low dose group (NL Group, 10 µmol/kg), medium dose group (NM Group, 50µmol/kg) and high dose group (NH Group, 100 µmol/kg), 12 rats in each group. The drug treated groups were injected with NaHS intraperitoneally once a day for 4 weeks. The changes of learning and memory ability of SCA3 mice before and after the intervention of different doses of NaHS were determined by Morris water maze, the content of hydrogen sulfide (H2S) in hippocampus was measured by spectrophotometry, the expression of MBP was detected by immunohistochemistry, and the morphological changes of neuron myelin sheath were observed by electron microscope. Results: Compared with the control group, the learning and memory ability of SCA3 mice was decreased significantly (P<0.05), and the content of H2S in hippocampus was decreased (P<0.05). After different doses of exogenous NaHS treatment, the learning and memory ability was improved in different degrees (P<0.05), and the contents of H2S and MBP in hippocampus of SCA3 mice were also improved in different degrees (P<0.05). Conclusion: Exogenous NaHS may increase the contents of H2S and MBP in the hippocampus of SCA3 mice, which may have a protective effect on the neurons, and then improve the learning and memory ability of SCA3 mice, and provide a new idea for the treatment of SCA3.


Assuntos
Sulfeto de Hidrogênio , Aprendizagem , Memória , Ataxias Espinocerebelares , Sulfetos , Animais , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Proteína Básica da Mielina , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ataxias Espinocerebelares/tratamento farmacológico , Sulfetos/farmacologia , Sulfetos/uso terapêutico
15.
Chin Med J (Engl) ; 133(19): 2302-2307, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32881721

RESUMO

BACKGROUND: Data on the evolution of recent small sub-cortical infarcts are limited, especially in the Chinese. Previous studies have reported a large heterogeneity in cavitation and infarct location; therefore, the present study assessed the morphology of small sub-cortical infarcts in the basal ganglia in a Chinese cohort. METHODS: Patients who had experienced a recent, single, small sub-cortical infarct in the basal ganglia and received at least one follow-up magnetic resonance imaging (MRI) scan were retrospectively identified from January 2014 to June 2018. Time to follow-up imaging, baseline infarct size, vascular risk factors, and other clinical data, as well as the morphologic changes of the index infarct and surrounding white matter were recorded. Demographic, clinical and MRI characteristics were respectively compared among three groups (white matter hyper-intensitie [WMH] vs. cavitation vs. absent) and between with and without new WMH formation groups. In addition, logistic regression analyses were performed in investigating the determinate independent predictors for new WMH formation. RESULTS: Seventy-eight subjects were included with a median follow-up time of 304 days (range: 124-552 days). We found a significant reduction in infarct size at follow-up: 46 of 78 (59.0%) infarctions showed some degree of cavitation, 19 of 78 (24.4%) index lesions resembled non-cavitated WMH, and 13 of 78 (16.7%) infarcts had disappeared at follow-up MRI. No factors were found to be associated with differential outcomes of the infarcts. In addition, 8 of 78 (10.3%) patients demonstrated new WMH formation surrounding the index infarct; white matter progression (odds ratio = 15.95, 95% confidence interval = 1.65-153.99; P = 0.017) was an independent risk factor of new WMH formation. CONCLUSIONS: More than half of the small sub-cortical infarcts in the basal ganglia progressed to cavities, demonstrating that these infarcts can be reduced and go undetected. The presence of new WMH around the infarct may be indicative of the worsening progression of cerebral small vessel diseases. Additionally, white matter progression is an independent risk factor, which may be a potential therapeutic target.


Assuntos
Substância Branca , Gânglios da Base/diagnóstico por imagem , China , Humanos , Infarto , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Substância Branca/diagnóstico por imagem
16.
Breastfeed Med ; 15(11): 709-714, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32896162

RESUMO

Objective: Our study was performed to analyze the interrelationship between breastfeeding for the first 6 months of life and the incidence of febrile seizures (FS). Study Design: A case-control study was conducted in Renmin Hospital of Wuhan University. Three hundred thirty-six patients diagnosed with FS were enrolled as the case group, and 336 febrile children with matched age and gender were enrolled as the control group. Clinical information of all cases was collected from the Electronic Medical Record, including feeding patterns. The primary outcome was the difference of feeding modes between cases and controls, while the secondary outcome included the difference of feeding patterns between simple FS (SFS) and complex FS (CFS). Results: The 336 patients with FS comprised 294 with SFS and 42 with CFS. The difference in feeding methods between the case group and the control group was statistically significant, and children who were breastfed exclusively had a lower risk of suffering from FS compared with formula feeding (odds ratio [OR], 0.504 and 95% confidence interval [CI], 0.303-0.841); although partial breastfeeding exhibited a slight protective effect against FS, the protective role was not statistically significant (OR, 1.016 and 95% CI, 0.560-1.846). In addition, our dates showed that feeding mode was not a risk factor in the occurrence of SFS or CFS (p > 0.05). Conclusion: Our data confirm that exclusive breastfeeding is an independent protective factor that can reduce the occurrence of FS.


Assuntos
Aleitamento Materno , Convulsões Febris/prevenção & controle , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Fatores de Risco , Convulsões Febris/epidemiologia
17.
Cell Death Dis ; 11(9): 727, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908122

RESUMO

Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer's disease, Parkinson's disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.


Assuntos
Doenças do Sistema Nervoso/terapia , Doenças Neurodegenerativas/terapia , Ubiquitina-Proteína Ligases/uso terapêutico , Animais , Humanos , Ubiquitina-Proteína Ligases/farmacologia
19.
JAMA Neurol ; 77(6): 746-754, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32310270

RESUMO

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores. Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12). Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.


Assuntos
Predisposição Genética para Doença/genética , Glicoproteínas de Membrana/genética , N-Acetilgalactosaminiltransferases/genética , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Idoso , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , /genética
20.
Front Genet ; 11: 254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292418

RESUMO

Previous observational studies have shown that the serum uric acid (UA) level is decreased in persons with multiple sclerosis (MS). We used the two-sample Mendelian randomization (MR) method to determine whether the serum UA level is causally associated with the risk of MS. We screened 26 single-nucleotide polymorphisms (SNPs) in association with serum UA level (p < 5 × 10-8) from a large genome-wide meta-analysis involving 110,347 individuals. The SNP outcome effects were obtained from two large international genetic studies of MS involving 38,589 individuals and 27,148 individuals. A total of 18 SNPs, including nine proxy SNPs, were included in the MR analysis. The estimate based on SNP rs12498742 that explained the largest proportion of variance showed that the odds ratio (OR) of UA (per mg/dl increase) for MS was 1.00 [95% confidence interval (CI) 0.90-1.11; p = 0.96]. The main MR analysis based on the random effects inverse variance weighted method showed that the pooled OR was 1.05 (95% CI 0.92-1.19; p = 0.50). Although there was no evidence of net horizontal pleiotropy in MR-Egger regression (p = 0.48), excessive heterogeneity was found via Cochran's Q statistic (p = 9.6 × 10-4). The heterogeneity showed a substantial decrease after exclusion of two outlier SNPs (p = 0.17). The pooled ORs for the other MR methods ranged from 0.89 (95% CI 0.65-1.20; p = 0.45) to 1.05 (95% CI 0.96-1.14; p = 0.29). The results of sensitivity analyses and additional analyses all showed similar pooled estimates. MR analyses by using 81 MS -associated SNPs as instrumental variables showed that genetically predicted risk of MS was not significantly associated with serum UA level. The pooled OR was 1.00 (95% CI 0.99-1.02; p = 0.74) for the main MR analysis. This MR study does not support a causal effect of genetically determined serum UA level on the risk of MS, nor does it support a causal effect of genetically determined risk of MS on serum UA level.

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