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1.
BMC Public Health ; 22(1): 115, 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35039022

RESUMO

BACKGROUND: Cardiovascular diseases (CVDs) remain the leading cause of premature mortality and burden of diseases in the world. The Inner Mongolia Autonomous Region is located in northern China, constitute 17.66% individuals with Mongolian, which have unique diet and lifestyles. Therefore, the Inner Mongolian Healthy Aging Study (IMAGINS) was designed to explore risk factors for chronic diseases and evaluate the effectiveness of health management on CVDs in population at high-risk. METHODS: The IMAGINS is an ongoing and prospective cohort study of men and women aged ≥35 years from Inner Mongolian Autonomous Region, northern China. This study performed in investigating risk factors for CVDs, screening and providing health management strategy for high-risk population of CVDs. The IMAGINS began in September 2015 and scheduled to recruiting and follow-up outcome until 2030. For general population, a long-term follow-up will be conducted every 5 years to collect the information above and data on clinical outcomes. For high-risk population, comprehensive health managements were performed and scheduled to follow-up annually. All IMAGINS participants are followed for incident CVDs and death. DISCUSSION: The IMAGINS is designed to increase understanding how cardiovascular-related risk factors contribute to the development of CVDs and the positive effect of health management strategy for high-risk CVD participants. Key features of this study include (i) a carefully characterized cohort between high risk of CVDs and non-high risk population; (ii) detailed measurement of CVDs risk factors and health management strategies for high risk population; (iii) long-term follow-up of CVDs and death. The IMAGINS represents a good research opportunity to investigate clinical and genetic factors in high-risk population, might providing basis for the prevention and control of non-communicable diseases.

2.
Front Cardiovasc Med ; 8: 769198, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869686

RESUMO

Background: Observational studies have identified impaired lung function accessed by forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or the ratio of FEV1 over FVC (FEV1/FVC) as an independent risk factor for atrial fibrillation (AF). However, the result may be affected by confounders or reverse causality. Methods: We performed univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR to jointly estimate the causality of lung function with AF. Apart from the inverse variance weighted (IVW) approach as the main MR analysis, three complementary sensitive analyses approaches including MR-Egger regression, weighted median (WM) MR and Pleiotropy Residual Sum and Outlier (MR-PRESSO) in uvMR as well as mvMR-Egger and mvMR-PRESSO in mvMR were applied to control for pleiotropy. Linkage disequilibrium score (LDSC) regression was applied to estimate genetic correlation between lung function and AF. Results: All forward and reverse uvMR analyses consistently suggested absent causal relations between lung function and AF risk [forward IVW: odds ratio (OR)FEV1 = 1.031, 95% CI = 0.909-1.169, P = 0.630; ORFVC = 1.002, 95% CI = 0.834-1.204, P = 0.982; ORFEV1/FVC = 1.076, 95% CI = 0.966-1.199, P = 0.182; reverse IVW: ORFEV1 = 0.986, 95% CI = 0.966-1.007, P = 0.187; ORFVC = 0.985, 95% CI = 0.965-1.006, P = 0.158; ORFEV1/FVC = 0.994, 95% CI = 0.973-1.015, P = 0.545]. The forward MR-Egger showed that each standard deviation (SD) increase in FEV1/FVC was related to a higher AF risk (OR = 1.502, 95% CI = 1.178-1.915, P = 0.006) without heterogeneity (Q_pval = 0.064), but pleiotropy effect exist (intercept = -0.017, P = 0.012). However, this significant effect disappeared after adjustment of FEV1 and FVC (OR = 1.523, 95% CI = 0.445-5.217, P = 0.503) in mvMR. No evidence was found for independent causal effects of FEV1 and FVC on AF in mvMR analysis by using mvIVW method (ORFEV1 = 0.501, 95% CI = 0.056-4.457, P = 0.496; ORFVC = 1.969, 95% CI = 0.288-13.474, P = 0.490). Notably, the association between lung function and AF were replicated using the FinnGen cohort data. Conclusions: Our findings reported no coheritability between lung function and AF, and failed to find substantial causal relation between decreased lung function and risk of AF. However, lung function and AF were both associated with inflammation, which may be potential pathway, warranting further study.

3.
EPMA J ; 12(4): 517-534, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34956424

RESUMO

Background: Pregnant women, particularly in developing countries are facing a huge burden of preeclampsia (PE) leading to high morbidity and mortality rates. This is due to delayed diagnosis and unrecognised early targeted preventive measures. Adapting innovative solutions via shifting from delayed to early diagnosis of PE in the context of predictive diagnosis, targeted prevention and personalisation of medical care (PPPM/3 PM) is essential. The subjective assessment of suboptimal health status (SHS) and objective biomarkers of oxidative stress (OS) and angiogenic growth mediators (AGMs) could be used as new PPPM approach for PE; however, these factors have only been studied in isolation with no data on their combine assessment. This study profiled early gestational biomarkers of OS and AGMs as 3 PM approach to identify SHS pregnant mothers likely to develop PE specifically, early-onset PE (EO-PE) and late-onset PE (LO-PE). Methods: A prospective cohort of 593 singleton normotensive pregnant (NTN-P) women were recruited at 10-20th (visit 1) and followed from 21 weeks gestation until the time of PE diagnosis and delivery. At visit 1, SHS was assessed using SHS questionnaire-25 (SHSQ-25) and women were classified as SHS and optimal health status (OHS). Biomarkers of OS (8-hydroxy-2-deoxyguanosine [8-OHdG], 8-epi-prostaglansinF2alpha [8-epi-PGF2α] and total antioxidant capacity [TAC]) and AGMs (vascular endothelial growth factor [VEGF-A], soluble Fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF] and soluble endoglin [sEng]) were measured at visit 1 and time of PE diagnosis. Results: Of the 593 mothers, 498 (248 SHS and 250 OHS) returned for delivery and were included in the final analysis. Fifty-six, 97 and 95 of the 248 SHS mothers developed EO-PE, LO-PE and NTN-P respectively, versus 14 EO-PE, 30 LO-PE and 206 NTN-P among the 250 OHS mothers. At the 10-20th week gestation, unbalanced levels of OS and AGMs were observed among SHS women who developed EO-PE than LO-PE compared to NTN-P women (p < 0.0001). The combined ratios of OS and AGMs, mainly the levels of 8-OHdG/PIGF ratio at 10-20th week gestation yielded the best area under the curve (AUC) and highest relative risk (RR) for predicting SHS-pregnant women who developed EO-PE (AUC = 0.93; RR = 6.5; p < 0.0001) and LO-PE (AUC = 0.88, RR = 4.4; p < 0.0001), as well as for OHS-pregnant women who developed EO-PE (AUC = 0.89, RR = 5.6; p < 0.0001) and LO-PE (AUC = 0.85; RR = 5.1; p < 0.0001). Conclusion: Unlike OHS pregnant women, SHS pregnant women have high incidence of PE coupled with unbalanced levels of OS and AGMs at 10-20 weeks gestation. Combining early gestational profiling of OS and AGMs created an avenue for early differentiation of PE subtypes in the context of 3 PM care for mothers at high risk of PE.

4.
Pharmgenomics Pers Med ; 14: 1565-1574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34898995

RESUMO

Background: Protein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese. Methods: In a case-control study with a total of 541 PLC patients and 547 controls in Guangxi province of Southern China, we genotyped six putatively functional polymorphisms (rs10421191G>A, rs11453459del>insG, rs1560092T>G, rs7840855C>T, rs1255722G>A and rs10151527A>C) of three PP2A subunit genes (PPP2R1A, PPP2R2A and PPP2R5E) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform. Results: The rs11453459insG variant genotypes (ins/ins+del/ins) of PPP2R1A were found to be significantly associated with an increased risk of PLC compared with the del/del genotype (adjusted OR = 1.290, 95% CI = 1.009-1.650), and the number of insert G allele worked in a dose-dependent manner (P trend= 0.007). The stratified analysis showed that the effects of rs11453459insG variant genotypes were more evident in the subgroup who drink pond-ditch water (adjusted OR = 3.051, 95% CI = 1.264-7.364) than those never drink (P = 0.041). The carriers of rs11453459 del/ins genotype had a significantly lower level of PPP2R1A mRNA expression in liver cancer tissues than those of the del/del genotype (P = 0.021). Furthermore, we used microcystin-LR, a carcinogen presents in the pond-ditch water, to treat human peripheral blood mononuclear cells and found that the cells from carriers of rs11453459insG variant genotypes induced more DNA oxidative damages than those from the del/del genotype carriers (P < 0.001). Conclusion: These findings suggest that the PPP2R1A rs11453459del>insG polymorphism is associated with an increased risk of PLC, especially for persons with a history of drinking pond-ditch water. This insertion/deletion polymorphism may be a susceptible biomarker for PLC in Chinese.

5.
Front Immunol ; 12: 741705, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804021

RESUMO

Genome-wide association studies (GWAS) have identified over 60 genetic loci associated with immunoglobulin G (IgG) N-glycosylation; however, the causal genes and their abundance in relevant tissues are uncertain. Leveraging data from GWAS summary statistics for 8,090 Europeans, and large-scale expression quantitative trait loci (eQTL) data from the genotype-tissue expression of 53 types of tissues (GTEx v7), we derived a linkage disequilibrium score for the specific expression of genes (LDSC-SEG) and conducted a transcriptome-wide association study (TWAS). We identified 55 gene associations whose predicted levels of expression were significantly associated with IgG N-glycosylation in 14 tissues. Three working scenarios, i.e., tissue-specific, pleiotropic, and coassociated, were observed for candidate genetic predisposition affecting IgG N-glycosylation traits. Furthermore, pathway enrichment showed several IgG N-glycosylation-related pathways, such as asparagine N-linked glycosylation, N-glycan biosynthesis and transport to the Golgi and subsequent modification. Through phenome-wide association studies (PheWAS), most genetic variants underlying TWAS hits were found to be correlated with health measures (height, waist-hip ratio, systolic blood pressure) and diseases, such as systemic lupus erythematosus, inflammatory bowel disease, and Parkinson's disease, which are related to IgG N-glycosylation. Our study provides an atlas of genetic regulatory loci and their target genes within functionally relevant tissues, for further studies on the mechanisms of IgG N-glycosylation and its related diseases.

6.
Front Immunol ; 12: 748566, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630427

RESUMO

Coronavirus disease 2019 (COVID-19) remains a major health challenge globally. Previous studies have suggested that changes in the glycosylation of IgG are closely associated with the severity of COVID-19. This study aimed to compare the profiles of IgG N-glycome between COVID-19 patients and healthy controls. A case-control study was conducted, in which 104 COVID-19 patients and 104 age- and sex-matched healthy individuals were recruited. Serum IgG N-glycome composition was analyzed by hydrophilic interaction liquid chromatography with the ultra-high-performance liquid chromatography (HILIC-UPLC) approach. COVID-19 patients have a decreased level of IgG fucosylation, which upregulates antibody-dependent cell cytotoxicity (ADCC) in acute immune responses. In severe cases, a low level of IgG sialylation contributes to the ADCC-regulated enhancement of inflammatory cytokines. The decreases in sialylation and galactosylation play a role in COVID-19 pathogenesis via the activation of the lectin-initiated alternative complement pathway. IgG N-glycosylation underlines the complex clinical phenotypes of SARS-CoV-2 infection.


Assuntos
COVID-19/metabolismo , Imunoglobulina G/metabolismo , SARS-CoV-2/fisiologia , Adulto , Citotoxicidade Celular Dependente de Anticorpos , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Lectina de Ligação a Manose da Via do Complemento , Feminino , Glicosilação , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
7.
EPMA J ; : 1-31, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34539937

RESUMO

First two decades of the twenty-first century are characterised by epidemics of non-communicable diseases such as many hundreds of millions of patients diagnosed with cardiovascular diseases and the type 2 diabetes mellitus, breast, lung, liver and prostate malignancies, neurological, sleep, mood and eye disorders, amongst others. Consequent socio-economic burden is tremendous. Unprecedented decrease in age of maladaptive individuals has been reported. The absolute majority of expanding non-communicable disorders carry a chronic character, over a couple of years progressing from reversible suboptimal health conditions to irreversible severe pathologies and cascading collateral complications. The time-frame between onset of SHS and clinical manifestation of associated disorders is the operational area for an application of reliable risk assessment tools and predictive diagnostics followed by the cost-effective targeted prevention and treatments tailored to the person. This article demonstrates advanced strategies in bio/medical sciences and healthcare focused on suboptimal health conditions in the frame-work of Predictive, Preventive and Personalised Medicine (3PM/PPPM). Potential benefits in healthcare systems and for society at large include but are not restricted to an improved life-quality of major populations and socio-economical groups, advanced professionalism of healthcare-givers and sustainable healthcare economy. Amongst others, following medical areas are proposed to strongly benefit from PPPM strategies applied to the identification and treatment of suboptimal health conditions:Stress overload associated pathologiesMale and female healthPlanned pregnanciesPeriodontal healthEye disordersInflammatory disorders, wound healing and pain management with associated complicationsMetabolic disorders and suboptimal body weightCardiovascular pathologiesCancersStroke, particularly of unknown aetiology and in young individualsSleep medicineSports medicineImproved individual outcomes under pandemic conditions such as COVID-19.

8.
Epigenetics ; : 1-13, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34461811

RESUMO

Previous genome-wide association studies (GWAS) have identified potential genetic variants involved in the risk of Alzheimer's dementia, but their underlying biological interpretation remains largely unclear. In addition, the effects of DNA methylation and gene expression on Alzheimer's dementia are not well understood. A network summary data-based Mendelian randomization (SMR) analysis was performed integrating cis- DNA methylation quantitative trait loci (mQTL) /cis- gene expression QTL (eQTL) data in the brain and blood, as well as GWAS summarized data for Alzheimer's dementia to evaluate the pleiotropic associations of DNA methylation and gene expression with Alzheimer's dementia and to explore the complex mechanisms underpinning Alzheimer's dementia. After correction for multiple testing (false discovery rate [FDR] P < 0.05) and filtering using the heterogeneity in dependent instruments (HEIDI) test (PHEIDI>0.01), we identified dozens of DNA methylation sites and genes showing pleiotropic associations with Alzheimer's dementia. We found 22 and 16 potentially causal pathways of Alzheimer's dementia (i.e., SNP→DNA methylation→Gene expression→Alzheimer's dementia) in the brain and blood, respectively. Approximately two-thirds of the identified DNA methylation sites had an influence on gene expression and the expression of almost all the identified genes was regulated by DNA methylation. Our network SMR analysis provided evidence supporting the pleiotropic association of some novel DNA methylation sites and genes with Alzheimer's dementia and revealed possible causal pathways underlying the pathogenesis of Alzheimer's dementia. Our findings shed light on the role of DNA methylation in gene expression and in the development of Alzheimer's dementia.

9.
Lipids Health Dis ; 20(1): 71, 2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273996

RESUMO

BACKGROUND: Some previous studies on different populations have yielded inconsistent findings with respect to the relationship between levels of high-density lipoprotein cholesterol (HDL-C) and future type 2 diabetes mellitus (T2DM) incidence. This study was designed to gain further insight into this relationship through a cohort study with a 25-year follow-up duration. METHODS: In total, 1462 individuals that were 55 years of age or older and were free of T2DM at baseline were enrolled in the present study. T2DM incidence among this study population was detected through self-reported diagnoses or the concentration of fasting plasma glucose. The data were derived from nine surveys conducted from 1992 to 2017. The correlation between HDL-C levels and the T2DM risk was assessed through Cox proportional-hazards model and proportional hazards model for the sub-distribution with time-dependent variables. RESULTS: Over the follow-up period, 120 participants were newly diagnosed with new-onset T2DM. When research participants were separated into four groups on the basis for quartiles of their levels of HDL-C measured at baseline, and incidence of diabetes declined with higher baseline HDL-C levels at 12.60, 9.70, 5.38, and 5.22 per 1000 person-years, respectively. Adjusted hazard ratios (HRs) were 0.98 (95% confidence interval [CI]: 0.62-1.55), 0.48 (95% CI: 0.27-0.85) and 0.44 (95% CI: 0.25-0.80) for individuals with HDL-C levels within the 1.15-1.39, 1.40-1.69, and ≥ 1.70 mmol/L ranges relative to participants with HDL-C levels < 1.15 mmol/L. Multiple sensitivity analyses similarly revealed reduced risk of diabetes incidence with increased HDL-C levels. Incorporating the levels of HDL-C into a multivariate model significantly enhanced the overall power of the predictive model (P values were 0.0296, 0.0011, respectively, for 5- and 10-year risk of diabetes). CONCLUSIONS: Levels of HDL-C were independently and negatively associated with the risk of the new-onset T2DM among middle-aged and elderly Chinese.

10.
EPMA J ; 12(2): 103-115, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34194583

RESUMO

The early identification of Suboptimal Health Status (SHS) creates a window opportunity for the predictive, preventive, and personalized medicine (PPPM) in chronic diseases. Previous studies have observed the alterations in several mRNA levels in SHS individuals. As a promising "omics" technology offering comprehension of genome structure and function at RNA level, transcriptome profiling can provide innovative molecular biomarkers for the predictive identification and targeted prevention of SHS. To explore the potential biomarkers, biological functions, and signalling pathways involved in SHS, an RNA sequencing (RNA-Seq)-based transcriptome analysis was firstly conducted on buffy coat samples collected from 30 participants with SHS and 30 age- and sex-matched healthy controls. Transcriptome analysis identified a total of 46 differentially expressed genes (DEGs), in which 22 transcripts were significantly increased and 24 transcripts were decreased in the SHS group. A total of 23 transcripts were selected as candidate predictive biomarkers for SHS. Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that several biological processes were related to SHS, such as ATP-binding cassette (ABC) transporter and neurodegeneration. Protein-protein interaction (PPI) network analysis identified 10 hub genes related to SHS, including GJA1, TWIST2, KRT1, TUBB3, AMHR2, BMP10, MT3, BMPER, NTM, and TMEM98. A transcriptome predictive model can distinguish SHS individuals from the healthy controls with a sensitivity of 83.3% (95% confidence interval (CI): 73.9-92.7%), a specificity of 90.0% (95% CI: 82.4-97.6%), and an area under the receiver operating characteristic curve of 0.938 (95% CI: 0.882-0.994). In the present study, we demonstrated that blood (buffy coat) samples appear to be a very promising and easily accessible biological material for the transcriptomic analyses focused on the objective identification of SHS by using our transcriptome predictive model. The pattern of particularly determined DEGs can be used as predictive transcriptomic biomarkers for the identification of SHS in an individual who may, subjectively, feel healthy, but at the level of subcellular mechanisms, the changes can provide early information about potential health problems in this person. Our findings also indicate the potential therapeutic targets in dealing with chronic diseases related to SHS, such as T2DM and CVD, and an early onset of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, as well as the findings suggest the targets for personalized interventions as promoted in PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-021-00238-1.

11.
Invest Ophthalmol Vis Sci ; 62(9): 26, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279570

RESUMO

Purpose: To explore the associations between macular choroidal and retinal thickness and axial elongation in non-myopic and myopic junior students. Methods: In this school-based longitudinal observational study, axial length was measured by optical low-coherence reflectometry, and choroidal thickness and retinal thickness were measured by spectral-domain optical coherence tomography. Myopia was defined as non-cycloplegic objective spherical equivalent refraction ≤ -0.50 diopters. Structural equation modeling and multiple linear regression models were used to analyze the associations between baseline choroidal and retinal thickness with axial elongation. Results: Out of 1307 students examined at baseline in 2017, 1197 (91.58%) returned for follow-up examination in 2018, with a median age of 12.00 years (interquartile range [IQR], 1.00) and included 667 boys (55.72%). Within a 1-year period, the median axial elongation of right eyes was 230 µm (IQR, 180) in boys and 200 µm (IQR, 160) in girls (P = 0.032). The thinner temporal choroidal thickness was associated with greater 1-year axial elongation only in myopic students (ß, -0.20; 95% confidence interval [CI], -0.37, -0.03), the thinner temporal retinal thickness was associated with greater 1-year axial elongation in both non-myopic (ß, -2.67; 95% CI, -4.52, -0.82) and myopic (ß, -0.99; 95% CI, -1.68, -0.30) students, after adjustment for sex, age, and height. Subfoveal and nasal choroidal and retinal thickness were not significantly associated with axial elongation in either non-myopic or myopic students. Conclusions: A thinner temporal choroid at age 12 years may predict greater 1-year axial elongation in myopic students, and a thinner temporal retina may predict greater 1-year axial elongation in both non-myopic and myopic students. This finding may help to identify children at risk and control axial elongation with potential preventive strategies.


Assuntos
Comprimento Axial do Olho/patologia , Corioide/patologia , Miopia/diagnóstico , Refração Ocular/fisiologia , Retina/patologia , Estudantes , Tomografia de Coerência Óptica/métodos , Adolescente , Pequim/epidemiologia , Criança , Feminino , Humanos , Incidência , Masculino , Miopia/epidemiologia , Miopia/fisiopatologia , Testes Visuais , Acuidade Visual
12.
Health Qual Life Outcomes ; 19(1): 180, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281537

RESUMO

BACKGROUND: The Suboptimal Health Status Questionnaire-25 (SHS-Q-25) developed to measure Suboptimal Health Status has been used worldwide, but its construct validity has only been tested in the Chinese population. Applying Structural Equation Modelling, we investigate aspects of the construct validity of the SHS-Q-25 to determine the interactions between SHS subscales in a Ghanaian population. METHODS: The study involved healthy Ghanaian participants (n = 263; aged 20-80 years; 63% female), who responded to the SHSQ-25. In an exploratory factor and parallel analysis, the study extracted a new domain structure and compared to the established five-domain structure of SHSQ-25. A confirmatory factor analysis (CFA) was conducted and the fit of the model further discussed. Invariance analysis was carried out to establish the consistency of the instrument across multi-groups. RESULTS: The extracted domains were reliable with Cronbach's [Formula: see text] of 0.846, 0.820 and 0.864 respectively, for fatigue, immune-cardiovascular and cognitive. The CFA revealed that the model fit indices were excellent [Formula: see text]. The fit indices for the three-domain model were statistically superior to the five-domain model. There were, however, issues of insufficient discriminant validity as some average variance extracts were smaller than the corresponding maximum shared variance. The three-domain model was invariant for all constrained aspects of the structural model across age, which is an important risk factor for most chronic diseases. CONCLUSION: The validity tests suggest that the SHS-Q25 can measure SHS in a Ghanaian population. It can be recommended as a screening tool to early detect chronic diseases especially in developing countries where access to facilities is diminished.


Assuntos
Nível de Saúde , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Fatorial , Feminino , Gana , Humanos , Análise de Classes Latentes , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
13.
J Pers Med ; 11(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209622

RESUMO

OBJECTIVES: Hypertension and type 2 diabetes mellitus comorbidity (HDC) is common, which confers a higher risk of cardiovascular disease than the presence of either condition alone. Describing the underlying glycomic changes of immunoglobulin G (IgG) that predispose individuals to HDC may help develop novel protective immune-targeted and anti-inflammatory therapies. Therefore, we investigated glycosylation changes of IgG associated with HDC. METHODS: The IgG N-glycan profiles of 883 plasma samples from the three northwestern Chinese Muslim ethnic minorities and the Han Chinese were analyzed by ultra-performance liquid chromatography instrument. RESULTS: We found that 12 and six IgG N-glycan traits showed significant associations with HDC in the Chinese Muslim ethnic minorities and the Han Chinese, respectively, after adjustment for potential confounders and false discovery rate. Adding the IgG N-glycan traits to the baseline models, the area under the receiver operating characteristic curves (AUCs) of the combined models differentiating HDC from hypertension (HTN), type 2 diabetes mellitus (T2DM), and healthy individuals were 0.717, 0.747, and 0.786 in the pooled samples of Chinese Muslim ethnic minorities, and 0.828, 0.689, and 0.901 in the Han Chinese, respectively, showing improved discriminating performance than both the baseline models and the glycan-based models. CONCLUSION: Altered IgG N-glycan profiles were shown to associate with HDC, suggesting the involvement of inflammatory processes of IgG glycosylation. The alterations of IgG N-glycome, illustrated here for the first time in HDC, demonstrate a biomarker potential, which may shed light on future studies investigating their potential for monitoring or preventing the progression from HTN or T2DM towards HDC.

14.
BMJ Open ; 11(6): e049762, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108173

RESUMO

INTRODUCTION: Profiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%-40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk. METHODS AND ANALYSIS: The prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness-implementation hybrid design, taking place in the UK and China. People are eligible if they are 55-75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention. ETHICS AND DISSEMINATION: The PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London-Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People's Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN15986016.


Assuntos
Telefone Celular , Demência , Aplicativos Móveis , Idoso , China , Demência/prevenção & controle , Humanos , Londres , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Cancer Med ; 10(11): 3689-3699, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33960694

RESUMO

The marked overexpression of cyclin-dependent kinase 5 (CDK5) or Notch1 receptor, which plays critical roles in pancreatic ductal adenocarcinoma (PDAC) development, has been detected in numerous PDAC cell lines and tissues. Although, a previous study has demonstrated that CDK5 inhibition disrupts Notch1 functions in human umbilical vein endothelial cells, the mechanism underlying Notch1 activation regulated by CDK5 remains unclear. Herein, we identified a physical interaction between CDK5 and Notch1 in PDAC cells, with the Notch1 peptide phosphorylated by CDK5/p25 kinase. CDK5 blockade resulted in the profound inhibition of Notch signaling. Accordingly, CDK5 inhibition sensitized PDAC cell proliferation and migration following Notch inhibition. In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration. The combinational inhibition of CDK5 and Notch signaling may be an effective strategy in the treatment of PDAC.

16.
Front Genet ; 12: 608714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613636

RESUMO

Background: The causal association of C-reactive protein (CRP) and fibrinogen on intracerebral hemorrhage (ICH) remains uncertain. We investigated the causal associations of CRP and fibrinogen with ICH using two-sample Mendelian randomization. Method: We used single-nucleotide polymorphisms associated with CRP and fibrinogen as instrumental variables. The summary data on ICH were obtained from the International Stroke Genetics Consortium (1,545 cases and 1,481 controls). Two-sample Mendelian randomization estimates were performed to assess with inverse-variance weighted and sensitive analyses methods including the weighted median, the penalized weighted median, pleiotropy residual sum and outlier (MR-PRESSO) approaches. MR-Egger regression was used to explore the pleiotropy. Results: The MR analyses indicated that genetically predicted CRP concentration was not associated with ICH, with an odds ratio (OR) of 1.263 (95% CI = 0.935-1.704, p = 0.127). Besides, genetically predicted fibrinogen concentration was not associated with an increased risk of ICH, with an OR of 0.879 (95% CI = 0.060-18.281; p = 0.933). No evidence of pleiotropic bias was detected by MR-Egger. The findings were overall robust in sensitivity analyses. Conclusions: Our findings did not support that CRP and fibrinogen are causally associated with the risk of ICH.

17.
NPJ Aging Mech Dis ; 7(1): 3, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542243

RESUMO

Immunoglobulin G (IgG) functionality can drastically change from anti- to proinflammatory by alterations in the IgG N-glycan patterns. Our previous studies have demonstrated that IgG N-glycans associated with the risk factors of dementia, such as aging, dyslipidemia, type 2 diabetes mellitus, hypertension, and ischemic stroke. Therefore, the aim is to investigate whether the effects of IgG N-glycan profiles on dementia exists in a Chinese Han population. A case-control study, including 81 patients with dementia, 81 age- and gender-matched controls with normal cognitive functioning (NC) and 108 non-matched controls with mild cognitive impairment (MCI) was performed. Plasma IgG N-glycans were separated by ultra-performance liquid chromatography. Fourteen glycan peaks reflecting decreased of sialylation and core fucosylation, and increased bisecting N-acetylglucosamine (GlcNAc) N-glycan structures were of statistically significant differences between dementia and NC groups after controlling for confounders (p < 0.05; q < 0.05). Similarly, the differences for these 14 initial glycans were statistically significant between AD and NC groups after adjusting for the effects of confounders (p < 0.05; q < 0.05). The area under the receiver operating curve (AUC) value of the model consisting of GP8, GP9, and GP14 was determined to distinguish dementia from NC group as 0.876 [95% confidence interval (CI): 0.815-0.923] and distinguish AD from NC group as 0.887 (95% CI: 0.819-0.936). Patients with dementia were of an elevated proinflammatory activity via the significant changes of IgG glycome. Therefore, IgG N-glycans might contribute to be potential novel biomarkers for the neurodegenerative process risk assessment of dementia.

18.
J Diabetes ; 13(8): 672-680, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33491329

RESUMO

BACKGROUND: The relationship of immunoglobulin G (IgG) glycosylation with diabetes and diabetic nephropathy has been reported, but its role in diabetic retinopathy (DR) remains unclear. We aimed to investigate and validate the association of IgG glycosylation with DR. METHODS: We analyzed the IgG N-linked glycosylation profile and primarily selected candidate glycans by lasso (least absolute shrinkage and selection operator) regression analysis in the discovery population. The findings were validated in the replication population using a binary logistics model. The association between the significant glycosylation panel and clinical features was illustrated with Spearman's coefficient. The results were confirmed by sensitivity analyses. RESULTS: Among 16 selected glycan candidates using lasso, two IgG glycans (GP15, GP20) and two derived traits (IGP32, IGP54) were identified and validated to be significantly associated with DR (P < .05), and the combined adjusted odds ratios (ORs) were 0.587, 0.613, 1.970, and 0.593, respectively. The glycosylation panel showed a weak correlation with clinical features, except for age. In addition, the results remained consistent when the subjects with prediabetes were excluded from the controls, and the adjusted ORs were 0.677, 0.738, 1.597, and 0.678 in the whole population. Furthermore, in the 1:3 rematched population, a significant association was observed, apart from GP20. CONCLUSIONS: The IgG glycosylation profile, reflecting an aging and pro-inflammatory status, was significantly associated with DR. The variation in the IgG glycome deserves more attention in diabetic complications.

19.
Neurobiol Aging ; 97: 18-27, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33120085

RESUMO

The pathogenesis of Alzheimer's disease (AD) remains largely unclear. Exploring the genetic/epigenetic loci showing pleiotropic association with the neuropathologies of AD may greatly enhance understanding of the mechanisms underlying the development of AD. In this study, using data from the Religious Orders Study and the Rush Memory and Aging Project, we undertook a Mendelian randomization approach integrating genome-wide association studies (GWASs) and DNA methylation quantitative trait locus data to explore pleiotropic epigenetic loci for AD neuropathologies, including amyloid-ß (Aß) load and tau-containing neurofibrillary tangle density. We performed GWASs of DNA methylation in brain tissues from 592 participants and mapped 60,595 cis-SNP-CpG pairs after correction for multiple testing. By linking cis-DNA methylation quantitative trait locus with GWAS results for Aß load and tau tangles, we identified 47 CpGs showing pleiotropic association with Aß load by the Mendelian randomization analysis. We then used gene expression data from 537 individuals and performed quantitative trait methylation analysis. We found that 18 of the 47 CpGs were in cis associated with 25 mRNAs/genes, comprising 41 unique CpG-mRNA/gene pairs. Our findings shed light on the role of DNA methylation in the pathogenesis of Aß.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Metilação de DNA , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Ilhas de CpG/genética , Feminino , Expressão Gênica , Pleiotropia Genética/genética , Humanos , Emaranhados Neurofibrilares/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas tau/metabolismo
20.
Cancer Prev Res (Phila) ; 14(3): 347-354, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33303693

RESUMO

This study aimed to investigate the association of IgG glycosylation and esophageal precancerosis for squamous cell carcinoma and determine its role in inflammation. Primary glycans selected by the least absolute shrinkage and selection operator (LASSO) algorithm were validated using univariate and multivariate logistics models plus restricted cubic spline functions. In total, 24 direct glycans and 27 derived traits were detected, among which four glycans and three derived traits were primarily selected. Then, GP5 (adjusted OR: 0.805), GP17 (adjusted OR: 1.305), G12n (adjusted OR: 1.271), Gal_1 (adjusted OR: 0.776) and Fuc (adjusted OR: 0.737) were validated and significantly associated with esophageal precancerosis. In addition, there was a consistent positive association in GP17 and G12n and a negative association in GP5, Gal_1, and Fuc by restricted cubic spline function. Compared with esophageal inflammation, GP17, G12n, and Fuc were still independently associated with precancerosis. In brief, the IgG glycosylation profile was independently associated with esophageal precancerosis beyond inflammation, which could be an early biomarker for esophageal cancer.Prevention Relevance: IgG glycosylation profile is associated with esophageal precancerosis and specific IgG glycans involves in the early stage of esophageal cancer, which is independent of inflammation.

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