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1.
Lipids Health Dis ; 19(1): 116, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32473635

RESUMO

BACKGROUND: Apolipoprotein CIII (apoCIII) is associated with triglyceride-rich lipoprotein metabolism and has emerged as independent marker for risk of cardiovascular disease. The objective was to test whether apoCIII is regulated postprandially and whether apoCIII concentrations in native and chylomicron-free serum predict future cardiovascular events in patients with stable coronary artery disease (CAD). METHODS: ApoCIII concentrations were measured in native and chylomicron-free serum in the fasting state and after a standardized oral fat load test in 195 patients with stable CAD. Clinical follow-up was 48 months. Chylomicron-free serum was prepared by ultracentrifugation (18,000 rpm, 3 h). The log-rank test and Cox regression analyses were used to investigate the association of apoCIII with recurrent cardiovascular events. RESULTS: Of the 195 patients included, 92 had a cardiovascular event, and 103 did not. 97% were treated with a statin. No significant changes in apoCIII concentration were observed after the oral fat load test. The apoCIII concentration was associated with event-free survival independent of conventional risk factors. This association reached statistical significance only for apoCIII concentration measured in chylomicron-free serum (hazard ratio [95% confidence interval] for apoCIII above the mean: postprandial: 1.67 (1.06-2.29), P = 0.028, fasting: 2.09 (1.32-3.32), P = 0.002), but not for apoCIII concentration measured in native serum (postprandial: 1.47 [0.89-2.43], P = 0.133, fasting: 1.56 [0.95-2.58], P = 0.081). The effects were independent of other risk factors. CONCLUSIONS: ApoCIII concentrations in chylomicron-free serum are independently associated with event-free survival in patients with CAD both in fasting and postprandial state. This findings support considering apoCIII for risk assessment and attempting to test the hypothesis that lowering apoCIII reduces residual cardiovascular risk. TAKE HOME MESSAGE: Apolipoprotein CIII concentration measured in chylomicron-free serum predicts recurrent cardiovascular events in patients with stable coronary artery disease. TRIAL REGISTRATION: The trial which included the participants of this study was registered at https://clinicaltrials.gov (NCT00628524) on March 5, 2008.


Assuntos
Apolipoproteína C-III/sangue , Apolipoproteínas C/sangue , Doenças Cardiovasculares/sangue , Doença da Artéria Coronariana/sangue , Adolescente , Adulto , Idoso , Apolipoproteína C-III/genética , Doenças Cardiovasculares/tratamento farmacológico , Doença da Artéria Coronariana/tratamento farmacológico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Estudos Prospectivos , Fatores de Risco , Triglicerídeos/sangue , Relação Cintura-Quadril/métodos , Adulto Jovem
2.
Nat Commun ; 10(1): 3310, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346172

RESUMO

Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Apolipoproteínas C/genética , Apolipoproteínas C/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Cognição , Feminino , Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Nectinas/genética , Nectinas/metabolismo , Polimorfismo de Nucleotídeo Único
3.
J Cell Biochem ; 120(10): 18246-18265, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31211449

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and lethal malignancies worldwide. Apolipoproteins (APOs) have been reported increasingly for their relationships with tumors. We aim at exploring the potential relationships of apolipoprotein A (APOA) and apolipoprotein C (APOC) family members with HCC. METHODS: A data set, containing 212 hepatitis B virus-related HCC patients, was used for analysis. The diagnostic and prognostic ability of APOA and APOC family genes was figured out. Risk score models and nomograms were developed for the HCC prognosis prediction. Moreover, molecular mechanism exploration were identified biological processes and metabolic pathways of these genes involved in. Validation analysis was carried out using online website. RESULTS: APOA1, APOC1, APOC3, and APOC4 showed robust diagnosis significance (all P < 0.05). APOA4, APOC3, and APOC4 were associated with the overall survival (OS) while APOA4 and APOC4 were linked to recurrence-free survival (RFS, all P ≤ 0.05). Risk score models and nomograms had the advantage of predicting OS and RFS for HCC. Molecular mechanism exploration indicated that these genes were involved in the steroid metabolic process, the PPAR signaling pathway, and fatty acid metabolism. Besides that, validation analysis revealed that APOC1 and APOC4 had an association with OS; and APOC3 was associated with OS and RFS (all P ≤ 0.05). CONCLUSIONS: APOA1, APOC1, APOC3, and APOC4 are likely to be potential diagnostic biomarkers and APOC3 and APOC4 are likely to be potential prognostic biomarkers for hepatitis B virus-related HCC. They may be involved in the steroid metabolic process, PPAR signaling pathway, and fatty acid metabolism.


Assuntos
Apolipoproteínas A/genética , Apolipoproteínas C/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Hepatite/complicações , Neoplasias Hepáticas/genética , RNA Mensageiro/genética , Apolipoproteínas A/metabolismo , Apolipoproteínas C/metabolismo , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes , Hepatite/virologia , Vírus da Hepatite B/fisiologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Nomogramas , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo
4.
PLoS One ; 14(3): e0214060, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913229

RESUMO

The apolipoprotein E-C1-C4-C2 gene cluster at 19q13.32 encodes four amphipathic apolipoproteins. The influence of APOE common polymorphisms on plasma lipid/lipoprotein profile, especially on LDL-related traits, is well recognized; however, little is known about the role of other genes/variants in this gene cluster. In this study, we evaluated the role of common and uncommon/rare genetic variation in this gene region on inter-individual variation in plasma lipoprotein levels in non-Hispanic Whites (NHWs) and African blacks (ABs). In the variant discovery step, the APOE, APOC1, APOC4, APOC2 genes were sequenced along with their flanking and hepatic control regions (HCR1 and HCR2) in 190 subjects with extreme HDL-C/TG levels. The next step involved the genotyping of 623 NHWs and 788 ABs for the identified uncommon/rare variants and common tagSNPs along with additional relevant SNPs selected from public resources, followed by association analyses with lipid traits. A total of 230 sequence variants, including 15 indels were identified, of which 65 were novel. A total of 70 QC-passed variants in NHWs and 108 QC-passed variants in ABs were included in the final association analyses. Single-site association analysis of SNPs with MAF>1% revealed 20 variants in NHWs and 24 variants in ABs showing evidence of association with at least one lipid trait, including several variants exhibiting independent associations from the established APOE polymorphism even after multiple-testing correction. Overall, our study has confirmed known associations and also identified novel associations in this genomic region with various lipid traits. Our data also support the contribution of both common and uncommon/rare variation in this gene region in affecting plasma lipid profile in the general population.


Assuntos
Apolipoproteína C-II/genética , Apolipoproteína C-I/genética , Apolipoproteínas C/genética , Apolipoproteínas E/genética , Lipoproteínas/sangue , Adulto , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/genética , Feminino , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , /genética
5.
Curr Opin Lipidol ; 30(2): 108-116, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30649022

RESUMO

PURPOSE OF REVIEW: Sepsis is a common syndrome of multiorgan system dysfunction caused by a dysregulated inflammatory response to an infection and is associated with high rates of mortality. Plasma lipid and lipoprotein levels and composition change profoundly during sepsis and have emerged as both biomarkers and potential therapeutic targets for this condition. The purpose of this article is to review recent progress in the understanding of the molecular regulation of lipid metabolism during sepsis. RECENT FINDINGS: Patients who experience greater declines in high-density lipoprotein during sepsis are at much greater risk of succumbing to organ failure and death. Although the causality of these findings remains unclear, all lipoprotein classes can sequester and prevent the excessive inflammation caused by pathogen-associated lipids during severe infections such as sepsis. This primordial innate immune function has been best characterized for high-density lipoproteins. Most importantly, results from human genetics and preclinical animal studies have suggested that several lipid treatment strategies, initially designed for atherosclerosis, may hold promise as therapies for sepsis. SUMMARY: Lipid and lipoprotein metabolism undergoes significant changes during sepsis. An improved understanding of the molecular regulation of these changes may lead to new opportunities for the treatment of sepsis.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Metabolismo dos Lipídeos/genética , Lipoproteínas HDL/sangue , Insuficiência de Múltiplos Órgãos/genética , Pró-Proteína Convertase 9/genética , Sepse/genética , Animais , Anticolesterolemiantes/uso terapêutico , Apolipoproteínas C/uso terapêutico , Biomarcadores/sangue , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/imunologia , Regulação da Expressão Gênica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunidade Inata , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/imunologia , Lipase Lipoproteica/sangue , Lipase Lipoproteica/genética , Lipase Lipoproteica/imunologia , Lipoproteínas HDL/genética , Lipoproteínas HDL/imunologia , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Pró-Proteína Convertase 9/sangue , Pró-Proteína Convertase 9/imunologia , Sepse/sangue , Sepse/tratamento farmacológico , Sepse/mortalidade , Análise de Sobrevida
6.
J Am Heart Assoc ; 7(16): e009545, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30369316

RESUMO

Background Macrophage cholesterol efflux to high-density lipoproteins ( HDLs ) is the first step of reverse cholesterol transport. The cholesterol efflux capacity ( CEC ) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome-wide association study approach, we aimed to identify pathways that regulate CEC in humans. Methods and Results We measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome-wide significant signals ( P<6.25×10-9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology ( CETP , LIPC , LPL , APOA 1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE /C1/C2/C4 variant ( rs141622900, P nonadjusted=1.0×10-11; P adjusted=8.8×10-9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP 1 CB / PLB 1 and RBFOX 3/ ENPP 7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome-wide association study . These analyses identified 27 significant CEC associations, implicating 5 additional loci ( GCKR , LIPG , PLTP , PPARA , and TRIB 1). Conclusions Our genome-wide association study identified common genetic variation at the APOE /C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL -based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.


Assuntos
Apolipoproteínas C/genética , Apolipoproteínas E/genética , HDL-Colesterol/metabolismo , Colesterol/metabolismo , Doença da Artéria Coronariana/genética , Macrófagos/metabolismo , Idoso , Apolipoproteína C-I/genética , Apolipoproteína C-II/genética , Canadá , Estudos de Casos e Controles , Doença da Artéria Coronariana/metabolismo , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
7.
Trends Pharmacol Sci ; 39(8): 733-747, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29970260

RESUMO

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations. Therapeutic modulation of dyslipidemia by inhibiting 3'-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is standard practice throughout the world. However, based on findings from Mendelian studies and genetic sequencing in prospective longitudinal cohorts from around the world, novel therapeutic targets regulating lipid and lipoprotein metabolism, such as apoprotein C3, angiopoietin-like proteins 3 and 4, and lipoprotein(a), have been identified. These targets may provide additional avenues to prevent and treat atherosclerotic disease. We therefore review these novel molecular targets by addressing available Mendelian and observational data, therapeutic agents in development, and early outcomes results.


Assuntos
Aterosclerose/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Acil Coenzima A/antagonistas & inibidores , Acil Coenzima A/genética , Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Animais , Apolipoproteínas C/genética , Apolipoproteínas C/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Terapia de Alvo Molecular , Estudos Prospectivos
8.
Circulation ; 138(3): 244-254, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29506984

RESUMO

BACKGROUND: Selected dyslipidemia guidelines recommend non-high-density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (apoB) as secondary targets to the primary target of low-density lipoprotein-cholesterol (LDL-C). After considering 2 LDL-C estimates that differ in accuracy, we examined: (1) how frequently non-HDL-C guideline targets could change management; and (2) the utility of apoB targets after meeting LDL-C and non-HDL-C targets. METHODS: We analyzed 2518 adults representative of the US population from the 2011 to 2012 National Health and Nutrition Examination Survey and 126 092 patients from the Very Large Database of Lipids study with apoB. We identified all individuals as well as those with high-risk clinical features, including coronary artery disease, diabetes mellitus, and metabolic syndrome who met very high- and high-risk guideline targets of LDL-C <70 and <100 mg/dL using Friedewald estimation (LDL-CF) and a novel, more accurate method (LDL-CN). Next, we examined those not meeting non-HDL-C (<100, <130 mg/dL) and apoB (<80, <100 mg/dL) guideline targets. In those meeting dual LDL-C and non-HDL-C targets (<70 and <100 mg/dL, respectively, or <100 and <130 mg/dL, respectively), we determined the proportion of individuals who did not meet guideline apoB targets (<80 or <100 mg/dL). RESULTS: A total of 7% to 9% and 31% to 36% of individuals had LDL-C <70 and <100 mg/dL, respectively. Among those with LDL-CF<70 mg/dL, 14% to 15% had non-HDL-C ≥100 mg/dL, and 7% to 8% had apoB ≥80 mg/dL. Among those with LDL-CF<100 mg/dL, 8% to 10% had non-HDL-C ≥130 mg/dL and 2% to 3% had apoB ≥100 mg/dL. In comparison, among those with LDL-CN<70 or 100 mg/dL, only ≈2% and ≈1% of individuals, respectively, had non-HDL-C and apoB values above guideline targets. Similar trends were upheld among those with high-risk clinical features: ≈0% to 3% of individuals with LDL-CN<70 mg/dL had non-HDL-C ≥100 mg/dL or apoB ≥80 mg/dL compared with 13% to 38% and 9% to 25%, respectively, in those with LDL-CF<70 mg/dL. With LDL-CF or LDL-CN<70 mg/dL and non-HDL-C <100 mg/dL, 0% to 1% had apoB ≥80 mg/dL. Among all dual LDL-CF or LDL-CN<100 mg/dL and non-HDL-C <130 mg/dL individuals, 0% to 0.4% had apoB ≥100 mg/dL. These findings were robust to sex, fasting status, and lipid-lowering therapy status. CONCLUSIONS: After more accurately estimating LDL-C, guideline-suggested non-HDL-C targets could alter management in only a small fraction of individuals, including those with coronary artery disease and other high-risk clinical features. Furthermore, current guideline-suggested apoB targets provide modest utility after meeting cholesterol targets. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01698489.


Assuntos
Apolipoproteínas B/sangue , Apolipoproteínas C/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica , Doença da Artéria Coronariana/diagnóstico , Dislipidemias/diagnóstico , Prática Clínica Baseada em Evidências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Risco
9.
Nature ; 555(7695): S23-S25, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29517035
11.
J Pediatr ; 183: 170-177.e1, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28139241

RESUMO

OBJECTIVE: To describe the clinical, biochemical, and genetic features of patients with congenital disorders of glycosylation (CDG) identified in Spain during the last 20 years. STUDY DESIGN: Patients were selected among those presenting with multisystem disease of unknown etiology. The isoforms of transferrin and of ApoC3 and dolichols were analyzed in serum; phosphomannomutase and mannosephosphate isomerase activities were measured in fibroblasts. Conventional or massive parallel sequencing (customized panel or Illumina Clinical-Exome Sequencing TruSight One Gene Panel) was used to identify genes and mutations. RESULTS: Ninety-seven patients were diagnosed with 18 different CDG. Eighty-nine patients had a type 1 transferrin profile; 8 patients had a type 2 transferrin profile, with 6 of them showing an alteration in the ApoC3 isoform profile. A total of 75% of the patients had PMM2-CDG presenting with a heterogeneous mutational spectrum. The remaining patients showed mutations in any of the following genes: MPI, PGM1, GFPT1, SRD5A3, DOLK, DPGAT1, ALG1, ALG6, RFT1, SSR4, B4GALT1, DPM1, COG6, COG7, COG8, ATP6V0A2, and CCDC115. CONCLUSION: Based on literature and on this population-based study of CDG, a comprehensive scheme including reported clinical signs of CDG is offered, which will hopefully reduce the timeframe from clinical suspicion to genetic confirmation. The different defects of CDG identified in Spain have contributed to expand the knowledge of CDG worldwide. A predominance of PMM2 deficiency was detected, with 5 novel PMM2 mutations being described.


Assuntos
Acetiltransferases/metabolismo , Apolipoproteínas C/metabolismo , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/epidemiologia , Acetiltransferases/genética , Apolipoproteínas C/genética , Estudos de Coortes , Bases de Dados Factuais , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Incidência , Recém-Nascido , Masculino , Mutação , Estudos Retrospectivos , Medição de Risco , Espanha/epidemiologia
12.
J Gastroenterol Hepatol ; 32(3): 667-676, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27547913

RESUMO

BACKGROUND AND AIMS: Concurrent fatty liver in hepatitis B virus (HBV)-infected patients without significant alcohol intake is a frequent and increasingly alarming problem because of the non-alcoholic fatty liver disease pandemic. The risk of HBV-related hepatocellular carcinoma (HCC) development was increased by concomitant obesity and diabetes. Direct evidence of the hepatocarcinogenic effect of fatty liver in chronic HBV remains elusive. We aimed to evaluate the risk of concurrent histologically proven fatty liver in HBV hepatocarcinogenesis. METHODS: We conducted a retrospective cohort study on a liver biopsy cohort of HBV-infected patients without significant alcohol intake to evaluate the prevalence of concurrent histologically proven fatty liver and its association with subsequent HCC development. We also examined nine polymorphisms on six non-alcoholic fatty liver disease-related candidate genes (ADIPOQ, APOC3, GCKR, LEPR, PNPLA3, and PPARG). RESULTS: Among 270 HBV-infected patients, concurrent fatty liver was found in 107 patients (39.6%) and was associated with metabolic risks, cirrhosis (P = 0.016) and PNPLA3 rs738409 CG/GG genotype (P = 0.002). At a median follow-up of 79.9 months, 11 patients (4.1%) developed HCC, and nine of them had concurrent fatty liver. By multivariable Cox analysis, concurrent fatty liver (HR 7.27, 95% confidence interval: 1.52-34.76; P = 0.013), age, cirrhosis, and APOC3 rs2854116 TC/CC genotype (HR 3.93, 95% confidence interval: 1.30-11.84; P = 0.013) were independent factors predicting HCC development. CONCLUSIONS: Concurrent fatty liver is common in HBV-infected patients and an independent risk factor potentiating HBV-associated HCC development by 7.3-fold. The risk of HBV-related HCC is increased by APOC3 gene polymorphism, and further characterization is required by its role.


Assuntos
Carcinoma Hepatocelular/etiologia , Hepatite B Crônica/complicações , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Adulto , Apolipoproteínas C/genética , Carcinoma Hepatocelular/epidemiologia , Estudos de Coortes , Complicações do Diabetes/complicações , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/complicações , Polimorfismo Genético , Prevalência , Estudos Retrospectivos , Risco , Fatores de Risco
13.
Eur Arch Psychiatry Clin Neurosci ; 267(3): 199-212, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27549216

RESUMO

Proteomic analyses facilitate the interpretation of molecular biomarker probes which are very helpful in diagnosing schizophrenia (SZ). In the current study, we attempt to test whether potential differences in plasma protein expressions in SZ and bipolar disorder (BD) are associated with cognitive deficits and their underlying brain structures. Forty-two plasma proteins of 29 SZ patients, 25 BD patients and 93 non-clinical controls were quantified and analysed using multiple reaction monitoring-based triple quadrupole mass spectrometry approach. We also computed group comparisons of protein expressions between patients and controls, and between SZ and BD patients, as well. Potential associations of protein levels with cognitive functioning (psychomotor speed, executive functioning, crystallised intelligence) as well as underlying brain volume in the hippocampus were explored, using bivariate correlation analyses. The main finding of this study was that apolipoprotein expression differed between patients and controls and that these alterations in both disease groups were putatively related to cognitive impairments as well as to hippocampus volumes. However, none of the protein level differences were related to clinical symptom severity. In summary, altered apolipoprotein expression in BD and SZ was linked to cognitive decline and underlying morphological changes in both disorders. Our results suggest that the detection of molecular patterns in association with cognitive performance and its underlying brain morphology is of great importance for understanding of the pathological mechanisms of SZ and BD, as well as for supporting the diagnosis and treatment of both disorders.


Assuntos
Apolipoproteínas C/metabolismo , Transtorno Bipolar/complicações , Transtorno Bipolar/patologia , Transtornos Cognitivos/etiologia , Hipocampo/metabolismo , Esquizofrenia/complicações , Esquizofrenia/patologia , Adulto , Proteínas Sanguíneas/metabolismo , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Estatística como Assunto
15.
Nutr Res ; 36(6): 564-74, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27188902

RESUMO

The hypothesis of the present study is that the polymorphisms in the APOC3, CEPT, ACE, and ACTN3 genes can affect the outcome of nutritional intervention and the plasma lipid profile of HIV+ patients. To test the hypothesis, genetic material was collected from buccal cells, and serum was collected for biochemical analysis. Sixty-five patients were analyzed. The incorporation of protease inhibitor (PI) was more frequent in women (77% vs 33% in men). Nutritional intervention improved anthropometric parameters independent of the genotype. Patients with the RR genotype for the ACTN3 R577X polymorphism had lower glycemia (RR = 95.4 ± 6.5 mg/dL, RX = 102.6 ± 10.6 mg/dL, XX = 110.1 ± 16.3 mg/dL; P = .03) and a greater reduction in low-density lipoproteins (LDL) after intervention (LDL: RR = -23.7 ± 15.8 mg/dL, RX = 1.32 ± 5.13 mg/dL, XX = 30.21 ± 24.4 mg/dL; P = .01). Patients using PI had a negative response to dietary intervention regarding the levels of high-density lipoprotein (-2.4 ± 1.70 with PI, 2.56 ± 1.60 mg/dL without PI; P = .02), very low density lipoprotein (0.84 ± 2.73 with IP, -5.46 ± 3.37 mg/dL without PI; P = .03), and triglycerides (1.79 ± 13.22 with PI, -34.00 ± 17.67 mg/dL without PI; P = .052). This response was also independent of the genotype (P > 0.05) and suggested the need for oral lipid-lowering drugs in all HIV+ patients using PI. Our results indicate that the ACTN3 R577X polymorphism is a good predictor of both the lipid profile and the prognosis of nutritional intervention in reducing LDL in HIV+ patients.


Assuntos
Actinina/genética , Infecções por HIV/dietoterapia , Infecções por HIV/genética , Desnutrição/dietoterapia , Polimorfismo de Nucleotídeo Único , Actinina/metabolismo , Adulto , Antropometria , Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , Apolipoproteínas C/sangue , Apolipoproteínas C/genética , Glicemia/metabolismo , Colesterol/sangue , Estudos de Coortes , Dieta , Feminino , Genótipo , Técnicas de Genotipagem , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Desnutrição/sangue , Desnutrição/etiologia , Desnutrição/genética , Pessoa de Meia-Idade , Mucosa Bucal/citologia , Mucosa Bucal/metabolismo , Avaliação Nutricional , Cooperação do Paciente , Triglicerídeos/sangue
16.
Orv Hetil ; 157(19): 746-52, 2016 May 08.
Artigo em Húngaro | MEDLINE | ID: mdl-27133274

RESUMO

The incidence and the public health importance of diabetes mellitus are growing continuously. Despite the improvement observed in recent years, the leading cause of morbidity and mortality of diabetics are cardiovascular diseases. The diagnosis of diabetes mellitus constitutes such a high risk as the known presence of vascular disease. Diabetic dyslipidaemia is characterised by high fasting and postprandial triglyceride levels, low HDL level, and slightly elevated LDL-cholesterol with domination of atherogenic small dense LDL. These are not independent components of the atherogenic dyslipidaemia, but are closely linked to each other. Beside the known harmful effects of low HDL and small dense LDL, recent findings confirmed the atherogenicity of the triglyceride-rich lipoproteins and their remnants. It has been shown that the key of this process is the overproduction and delayed clearance of triglyceride-rich lipoproteins in the liver. In this metabolism the lipoprotein lipase has a determining role; its function is accelerated by ApoA5 and attenuated by ApoC3. The null mutations of the ApoC3 results in a reduced risk of myocardial infarction, the loss-of-function mutation of ApoA5 was associated with a 60% elevation of triglyceride level and 2.2-times increased risk of myocardial infarction. In case of diabetes mellitus, insulin resistance, obesity, metabolic syndrome and chronic kidney disease the non-HDL-cholesterol is a better marker of the risk than the LDL-cholesterol. Its value can be calculated by subtraction of HDL-cholesterol from total cholesterol. Target values of non-HDL-cholesterol can be obtained by adding 0.8 mmol/L to the LDL-cholesterol targets (this means 3.3 mmol/L in high, and 2.6 mmol/L in very high risk patients). The drugs of first choice in the treatment of diabetic dyslipidaemia are statins. Nevertheless, it is known that even if statin therapy is optimal (treated to target), a considerable residual (lipid) risk remains. For its reduction treatment of low HDL-cholesterol and high triglyceride levels is obvious by the administration of fibrates. In addition to statin therapy, fenofibrate can be recommended.


Assuntos
Aterosclerose/etiologia , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/tratamento farmacológico , Dislipidemias/etiologia , Hipolipemiantes/uso terapêutico , Lipase Lipoproteica/metabolismo , Triglicerídeos/metabolismo , Apolipoproteína A-V , Apolipoproteínas A/metabolismo , Apolipoproteínas C/metabolismo , Aterosclerose/sangue , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/etiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Complicações do Diabetes/etiologia , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/sangue , Fenofibrato/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resistência à Insulina , Lipoproteínas/sangue , Síndrome Metabólica/complicações , Obesidade/complicações , Valor Preditivo dos Testes , Insuficiência Renal Crônica/complicações , Fatores de Risco , Triglicerídeos/sangue
17.
Rheumatology (Oxford) ; 55(8): 1421-30, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27094595

RESUMO

OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.


Assuntos
Apolipoproteína A-I/genética , Gota/genética , Família Multigênica/genética , Adulto , Apolipoproteína C-III/genética , Apolipoproteínas C/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Ácido Úrico/metabolismo , /genética
18.
J Proteomics ; 149: 44-52, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27109350

RESUMO

Intrauterine growth restriction (IUGR) is an important cause of perinatal morbidity and mortality and contributes substantially to medically indicated preterm birth; preventing fetal death. Molecular profiling of the mothers' peripheral blood was desired to monitor the health conditions of the fetuses. To develop such a minimally invasive assay, we applied a protein affinity fractionation method to peripheral blood serum samples from pregnant women belonging to either the IUGR or to the control group. Proof-of-principle was shown by relative quantitation analysis of mixtures of intact proteoforms using MALDI-ToF mass spectrometry. The two best differentiating proteins and proteoforms, respectively, were apolipoprotein C-II and apolipoprotein C-III0. Together with three robustly expressed protein proteoforms proapolipoprotein C-II, apolipoprotein C-III1, and apolipoprotein C-III2, which served as landmarks for relative quantitation analysis, they constituted the maternal IUGR proteome signature. Separation confidence of our IUGR proteoform signature reached a sensitivity of 0.73 and a specificity of 0.87 with an area under curve of 0.86 in receiver operator characteristics. SIGNIFICANCE: Identification of IUGR newborns in the case room is required as children are severely diseased and need specialized care during infancy. Yet, at time of birth there is no readily applicable clinical test available. Hence, a molecular profiling assay is highly desired. It needs to be mentioned that current clinical definitions and recommendations for IUGR are unfortunately misleading and are not universally applicable. The most commonly adopted definition is an abdominal circumference (AC) or estimated fetal weight measurement <10th percentile. Although both, the American College of Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetricians and Gynecologists (RCOG) agree that at this cut-off the risk of perinatal morbidity and mortality increases, this definition does not take into account the individualized growth potential of each fetus. In particular its sole use fails to identify larger fetuses that have not achieved their growth potential and may be at risk of adverse outcomes. Also, this definition, when solely applied, will result in the misdiagnosis of IUGR for some constitutionally small fetuses. It needs to be pointed out that the above mentioned criteria can only be determined during pregnancy in case mothers report from early on during pregnancy. We have developed a test that relies on mass spectrometric analysis of the mother's serum protein composition (IUGR signature) which can be determined just ahead of delivery and at date of delivery, respectively using a minimal invasive blood sampling approach. With this manuscript we describe the use of a mass spectrometric profiling method of 30 peripheral blood samples from pregnant women prior to giving birth of either unsuspicious newborns or IUGR-affected infants. We report for the first time that maternal blood sample analysis via affinity mass spectrometry differentiates IUGR infants from controls with high confidence.


Assuntos
Proteínas Sanguíneas/análise , Retardo do Crescimento Fetal/sangue , Proteoma/análise , Adulto , Apolipoproteínas C/sangue , Biomarcadores/sangue , Cromatografia de Afinidade/métodos , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Mortalidade Perinatal , Gravidez , Resultado da Gravidez , Fatores de Risco , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Estatísticas não Paramétricas
19.
Chem Phys Lipids ; 195: 63-70, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26756862

RESUMO

Lipoprotein lipase (LPL)-mediated triacylglycerol (TAG) hydrolysis in very low density lipoprotein (VLDL) is accompanied by the release of surface material containing phospholipids (PL), free cholesterol (FC) and apolipoproteins, E (apoE) and Cs (apoCII, apoCIII). The released molecules are accepted by high density lipoprotein (HDL), and new HDL-sized apoE-containing particles are also generated. A decrease in the number of HDL particles or abnormalities in their structure is associated with unfavourable changes in the features of VLDL remnants. Phosphatidylcholine liposomes (PC-L) can also act as acceptors of surface material components released from lipoproteins. Thus, the aim of this study was to assess the impact of liposomes on compositional changes of VLDL during its LPL-mediated lipolysis. VLDL isolated from human sera was incubated with LPL (LPL:VLDLTAG; 24 µg/ml:90 mg/dl) and/or PC-L (VLDLPL:PC-LPL; 1:30 weight ratio). After incubation (2h, 37 °C) VLDL was separated from other reaction products, and VLDL lipid and apolipoprotein content were analysed. Newly generated HDL-sized apoE-containing lipoproteins were separated by two-dimensional non-denaturing gradient gel electrophoresis (2D-PAGGE). The reaction of VLDL with PC-L in the presence or absence of LPL significantly affected the VLDL composition. The ratio of core (TAG+cholesteryl ester) to surface (PL+FC) lipids in VLDL decreased 1.8-fold with PC-L, 1.2-fold with LPL and 3-fold with PC-L+LPL. The reaction with PC-L and PC-L+LPL caused a 3.7-fold and 3.2-fold decrease of apoCs/apoE average weight ratio, respectively. Compositional changes in VLDL under the influence of PC-L were accompanied by an increase in the efficiency of VLDL lipolysis and the generation of apoE-containing HDL-sized particles, heterogeneous in size (from ∼ 9 to ∼ 18.8 nm) and mobility (γ and preß). We conclude that PL-rich particles, similarly to HDL, promote the release of surface material components from VLDL during LPL-mediated lipolysis and positively influence VLDL features which can facilitate VLDL metabolism. Such PC-L activity may impact on its antiatherogenic properties.


Assuntos
Lipase Lipoproteica/metabolismo , Lipossomos/metabolismo , Fosfatidilcolinas/química , Apolipoproteínas C/metabolismo , Apolipoproteínas E/metabolismo , Eletroforese em Gel Bidimensional , Humanos , Lipólise , Lipoproteínas VLDL/química , Lipoproteínas VLDL/metabolismo , Lipossomos/química
20.
Biometrics ; 72(2): 372-81, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26692376

RESUMO

Large assembled cohorts with banked biospecimens offer valuable opportunities to identify novel markers for risk prediction. When the outcome of interest is rare, an effective strategy to conserve limited biological resources while maintaining reasonable statistical power is the case cohort (CCH) sampling design, in which expensive markers are measured on a subset of cases and controls. However, the CCH design introduces significant analytical complexity due to outcome-dependent, finite-population sampling. Current methods for analyzing CCH studies focus primarily on the estimation of simple survival models with linear effects; testing and estimation procedures that can efficiently capture complex non-linear marker effects for CCH data remain elusive. In this article, we propose inverse probability weighted (IPW) variance component type tests for identifying important marker sets through a Cox proportional hazards kernel machine (CoxKM) regression framework previously considered for full cohort studies (Cai et al., 2011). The optimal choice of kernel, while vitally important to attain high power, is typically unknown for a given dataset. Thus, we also develop robust testing procedures that adaptively combine information from multiple kernels. The proposed IPW test statistics have complex null distributions that cannot easily be approximated explicitly. Furthermore, due to the correlation induced by CCH sampling, standard resampling methods such as the bootstrap fail to approximate the distribution correctly. We, therefore, propose a novel perturbation resampling scheme that can effectively recover the induced correlation structure. Results from extensive simulation studies suggest that the proposed IPW CoxKM testing procedures work well in finite samples. The proposed methods are further illustrated by application to a Danish CCH study of Apolipoprotein C-III markers on the risk of coronary heart disease.


Assuntos
Biomarcadores , Estudos de Coortes , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Apolipoproteínas C/análise , Biometria/métodos , Simulação por Computador , Doença das Coronárias/diagnóstico , Humanos , Medição de Risco/estatística & dados numéricos , Amostragem , Análise de Sobrevida
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