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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 769-776, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204930

RESUMO

OBJECTIVE: To explore the correlation of EB virus infection with the prognosis of B-ALL children. METHODS: The peripheral blood of children with newly diagnosed B-ALL admitted in Children's Hospital of Chongqing Medical University from January 2012 to December 2017 were collected, and the EBV DNA in plasma was detected by real-time quantitative PCR. The clinical data of B-ALL children were collected and the correlation of EBV infection with the prognosis of B-ALL children was analyzed. RESULTS: Among 162 B-ALL children, the EBV infection rate was 41.36%. Univariate analysis showed that the B-ALL children with EBV infection had the poor prognosis and higher risk of shorter survival time, as compared with B-ALL children without EBV infection (HR=2.373, 95% CI: 1.129-4.987) (P<0.05), the multivariate analysis showed that the result was consistent with result of univariate analysis indicating that EBV infection was an independent predictor for poor prognosis of B-ALL children. CONCLUSION: The EBV infection may play an important role in the occurrence and progression of B-ALL and is an independent predictor for poor prognosis, therefore the detection of EBV DNA in plasma of B-ALL children possesses an important significance for evaluation of B-ALL children's prognosis.


Assuntos
Infecções por Vírus Epstein-Barr , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfócitos B , Criança , DNA Viral , Herpesvirus Humano 4 , Humanos , Prognóstico
2.
Neurobiol Aging ; 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30954325

RESUMO

To identify novel loci that affect cognitive decline in older adults free of dementia, we conducted genome-wide and gene-based meta-analyses on longitudinal slopes of 5 cognitive domains (memory, executive function, language, attention/processing speed, and visuospatial ability) derived from 2 population-based cohorts. For decline over time in each cognitive domain, we normalized intraindividual slopes within each cohort, accounting for baseline age, sex, and years of education. Normalized slope for each domain was used in cohort-specific genome-wide analyses after including top principal components as covariates followed by genome-wide and gene-based meta-analyses. Both analyses revealed a novel WDFY2 locus at genome-wide (p = 3.37E-08) and gene-wide (p = 7.10E-07) significance levels for the attention/processing speed domain. In the GTEx eQTL analysis, genome-wide significant single-nucleotide polymorphism was associated with RNA expression levels of WDFY2 in several brain regions: cerebellar hemisphere (p = 1.07E-04), cerebellum (p = 6.92E-04), hippocampus (p = 2.18E-03) and cortex (p = 2.29E-02), and in whole blood (p = 4.41E-05). Our results suggest that WDFY2 genetic variation may affect individual differences in decline over time on tests of attention/processing speed.

3.
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.

4.
Curr Med Res Opin ; : 1-11, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30777458

RESUMO

OBJECTIVE: To compare the multi-biomarker disease activity (MBDA) score with the DAS28-CRP and CRP for predicting risk of radiographic progression in patients with rheumatoid arthritis. METHODS: Published studies of the MBDA score and radiographic progression with ≥100 patients per cohort were evaluated. Rates of radiographic progression over 1 year were determined across the low/moderate/high categories for MBDA score (low/moderate/high: <30, 30-44, >44), DAS28-CRP (low/moderate/high: ≤2.67, >2.67-4.09, >4.09) and CRP (low/moderate/high: ≤10, >10-30, >30 mg/L), with positive and negative predictive value (PPV, NPV) and relative risk (RR) determined for high vs. not-high (i.e. low and moderate combined) categories. Patient-level data from studies having all three measures was pooled to: (1) determine a combined RR for radiographic progression in the high vs. not-high categories for each measure; and (2) compare the predictive ability of MBDA score vs. DAS28-CRP by comparing the rates of radiographic progression observed in subgroups created by cross-classifying the high and not-high categories of each measure. RESULTS: Five cohorts were identified for inclusion (total N=929). In each, radiographic progression was more frequent with increasing MBDA scores. Among the three cohorts with requisite data, PPVs were generally similar using categories of MBDA score, DAS28-CRP or CRP but NPVs were greater for MBDA score (93-97%) than DAS28-CRP or CRP (77-87%). RRs for radiographic progression were greater when based on categories of MBDA score than DAS28-CRP or CRP and the combined RR was greater for MBDA score (4.6, p < .0001) than DAS28-CRP (1.7, p = .02) or CRP (1.7, p = .002). For patients cross-classified by MBDA score and DAS28-CRP, high vs. not-high MBDA score significantly predicted radiographic progression independently of DAS28-CRP. CONCLUSIONS: High and not-high MBDA scores were associated with increased and low risk, respectively, for radiographic progression over one year. MBDA score was a better predictor of radiographic progression than DAS28-CRP or CRP.

5.
Rheumatology (Oxford) ; 58(5): 874-883, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590790

RESUMO

OBJECTIVE: To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA. METHODS: Two models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS). RESULTS: Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true. CONCLUSION: Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.

6.
Mol Psychiatry ; 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361487

RESUMO

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; ß = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.

7.
Clin Rheumatol ; 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30159791

RESUMO

The Multi-Biomarker Disease Activity (MBDA) score is a validated rheumatoid arthritis (RA) disease activity measure based on 12 serum biomarkers. Here, we evaluate short-term biological variability of MBDA scores to determine the magnitude of change that might be considered clinically meaningful. Twenty-eight adult seropositive RA patients with clinically stable disease and no changes in RA medications for 4 weeks prior to study were enrolled. Nine serum samples were obtained over four consecutive days (non-fasting). MBDA score variation was assessed day-to-day (daily) and within 24 h (diurnal). The standard deviation (SD) of MBDA scores was calculated by a linear mixed model including random effects for patient, day, and time of day. The minimally important difference (MID) was calculated as [Formula: see text]. A subgroup analysis was performed for patients with active RA (moderate or high MBDA score). The SD of MBDA score change in the full cohort was 4.7 in a combined daily-diurnal variation analysis, which corresponds with an MID of 11. The SD of MBDA score change in the subset of patients with active RA (moderate/high MBDA scores) was 3.6. This corresponds with an MID of 8 units in patients with active RA for whom clinicians are most likely to need guidance with respect to therapeutic decisions. Changes in MBDA score ≥ 8 represent a change in RA disease activity that clinicians can use as a benchmark for therapeutic drug efficacy and can be incorporated into a treat-to-target strategy.

8.
Sci Rep ; 7: 45630, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28422128

RESUMO

Epidemiology and etiology of hand, foot, and mouth disease (HFMD) based on large sample size or evaluation of detection for more enterovirus serotypes are not well investigated in Chongqing of China. 45,616 suspect HFMD patients were prospectively enrolled among whom 21,615 were laboratory confirmed HFMD cases over a 5-year period (January 2011 to December 2015). Their epidemiological, clinical, and laboratory data were extracted and stratified by month, age, sex, disease severity, and enterovirus serotype. Subsequently 292 non-EV-A71/CV-A16 HFMD confirmed cases were randomly selected in three consecutive outbreaks to detect CV-A6 and CV-A10, using RT-PCR. Results showed that the HFMD epidemic peaked in early summer and autumn. The median age of onset was 2.45 years with a male-to-female ratio of 1.54:1, and with children under 5 years of age accounting for 92.54% of all confirmed cases. EV-A71 and CV-A16 infection accounted for only 36.05% (7793/21615) of total confirmed cases while EV-A71 accounted for 59.64% (232/389) of severe cases. Importantly, the proportion of EV-A71 infection generally increased with age which showed rapid growth in severe cases. CV-A6 and CV-A10 were tested positive in Chongqing, but CV-A6 had greater positive rates of 62.33% while CV-A10 had 4.79% in non-EV-A71/CV-A16 HFMD confirmed cases.

9.
J Med Genet ; 54(6): 381-389, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28289186

RESUMO

BACKGROUND: A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5 Mb) located at 8p23. Initially implicated genes included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported. OBJECTIVE AND METHODS: In this case -control study, we further investigated the 'extended' 8p23 locus (~ 4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~ 1200 subjects) and a replication data set (> 10 000 subjects) comprising European-descent individuals. RESULTS: Meta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10-8). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLK subregion), our results also revealed two 'new' SLE signals, including SGK223-CLDN23-MFHAS1 (6.06 × 10-9 ≤ meta p ≤ 4.88 × 10-8) and CTSB (meta p = 4.87 × 10-8) subregions that are located > 2 Mb upstream and ~ 0.3 Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative cis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background. CONCLUSIONS: Our results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways.


Assuntos
Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
10.
J Proteomics ; 154: 78-84, 2017 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-28007617

RESUMO

Traditional methods for thalassemia screening are time-consuming and easily affected by cell hemolysis or hemoglobin degradation in stored blood samples. Tandem mass spectrometry (MS/MS) proved to be an effective technology for sickle cell disorders (SCD) screening. Here, we developed a novel MS/MS method for ß-thalassemia screening from dried blood spots (DBS). Stable isotopic-labeled peptides were used as internal standards for quantification and calculation of the α:ß-globin ratios. We used the α:ß-globin ratio cutoffs to differentiate between normal individuals and patients with thalassemia. About 781 patients and 300 normal individuals were analyzed. The α:ß-globin ratios showed significant difference between normal and ß-thalassemia patients (P<0.01), particularly when the disease was homozygous or double heterozygous with another α- or ß-thalassemia mutation. In the parallel study, all cases screened for suspected thalassemia from six hundred DBS samples by using this MS/MS method were successfully confirmed by genotyping. The intra-assay and inter-assay CVs of the ratios ranged from 2.4% to 3.9% and 4.7% to 7.1%, and there was no significant sample carryover or matrix effect for this MS/MS method. Combined with SCD screening, this MS/MS method could be used as a first-line screening assay for both structural and expression abnormalities of human hemoglobin. BIOLOGICAL SIGNIFICANCE: Traditional methods for thalassemia screening were depending on the structural integrity of tetramers and could be affected by hemolysis and degradation of whole blood samples, especially when stored. We used proteospecific peptides produced by the tryptic digestion of each globin to evaluate the production ratio between α- and ß-globin chains, which turned out to be quite stable even when stored for more than two months. Though most of the peptides were specific to α-globin or ß-globin, we only chose four most informative peptides and its stable isotopic-labeled peptides as internal standards for analysis, which could obtain a high accuracy. Currently, we are the first to address the application of MS/MS for thalassemia screening, when combined with SCD screening, this MS/MS method could be used as a first-line screening assay for both structural and expression abnormalities of human hemoglobin.


Assuntos
Espectrometria de Massas em Tandem/métodos , Talassemia beta/diagnóstico , Coleta de Amostras Sanguíneas/métodos , Estudos de Casos e Controles , Genótipo , Humanos , Programas de Rastreamento/métodos , Sensibilidade e Especificidade , alfa-Globinas/análise , Globinas beta/análise , Talassemia beta/sangue
11.
Arthritis Rheumatol ; 68(1): 174-83, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26316170

RESUMO

OBJECTIVE: Genome-wide association studies (GWAS) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Followup studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in subjects of European descent. This multistage study was undertaken to identify novel SLE loci. METHODS: In stage 1, we conducted a new GWAS of SLE in a North American case-control sample of subjects of European ancestry (n = 1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional data set of subjects of European descent (>2,500 individuals), followed by replication of top meta-analysis findings in another data set of subjects of European descent (>10,000 individuals) in stage 3. RESULTS: As expected, our GWAS revealed the most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed the genome-wide significance threshold (P < 5 × 10(-8)). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also confirmed in the stage 1 discovery sample, and the strongest signals were observed at 2q32/STAT4 (P = 3.6 × 10(-7)) and at 8p23/BLK (P = 8.1 × 10(-6)). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P = 3.1 × 10(-8)), which was replicated in stage 3. CONCLUSION: Our multistage study identified and replicated a new SLE locus that warrants further followup in additional studies. Publicly available databases suggest that this newly identified SLE signal falls within a functionally relevant genomic region and near biologically important genes.


Assuntos
Cromossomos Humanos Par 12/genética , Grupo com Ancestrais do Continente Europeu/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Estudos de Casos e Controles , Caseína Quinase II/genética , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 8 , Simulação por Computador , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fator de Transcrição STAT4/genética , Tenascina/genética , Transcriptoma , Quinases da Família src/genética
12.
Metabolism ; 65(1): 36-47, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26683795

RESUMO

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a crucial role in lipid metabolism. Associations of common CETP variants with variation in plasma lipid levels, and/or CETP mass/activity have been extensively studied and well-documented; however, the effects of uncommon/rare CETP variants on plasma lipid profile remain undefined. Hence, resequencing of the gene in extreme phenotypes and follow-up rare-variant association analyses are essential to fill this gap. OBJECTIVE: To identify common and uncommon/rare variants in the CETP gene by resequencing the entire gene and test the effects of both common and uncommon/rare CETP variants on plasma lipid traits in two genetically distinct populations. METHODS AND RESULTS: The entire CETP gene plus flanking regions were resequenced in 190 individuals comprising 95 non-Hispanic whites (NHWs) and 95 African blacks with extreme HDL-C levels. A total of 279 sequence variants were identified, of which 25 were novel. Selected variants were genotyped in the entire samples of 623 NHWs and 788 African blacks and 184 QC-passed variants were tested in relation to plasma lipid traits by using gene-based, single-site, haplotype and rare variant association analyses (SKAT-O). Two novel and independent associations of rs1968905 and rs289740 with HDL-C were identified in African blacks. Using SKAT-O analysis, we also identified rare variants with minor allele frequency <0.01 to be associated with HDL-C in both NHWs (P=0.024) and African blacks (P=0.009). CONCLUSIONS: Our results point out that in addition to the common CETP variants, rare genetic variants in the CETP gene also contribute to the phenotypic variation of HDL-C in the general population.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , Grupo com Ancestrais do Continente Europeu/genética , Adulto , Idoso , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA
13.
BMC Med Genet ; 16: 106, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26563154

RESUMO

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) exerts many anti-atherogenic properties including its role in reverse cholesterol transport (RCT). Scavenger receptor class B member 1 (SCARB1) plays a key role in RCT by selective uptake of HDL cholesteryl esters. We aimed to explore the genetic contribution of SCARB1 to affecting lipid levels in African Blacks from Nigeria. METHODS: We resequenced 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels using Sanger method. Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods. A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits. RESULTS: The initial gene-based analysis demonstrated evidence of association with HDL-C and apolipoprotein A-I (ApoA-I). The follow-up single-site analysis revealed nominal evidence of novel associations of nine common variants with HDL-C and/or ApoA-I (P < 0.05). The strongest association was between rs11057851 and HDL-C (P = 0.0043), which remained significant after controlling for multiple testing using false discovery rate. Rare variant association testing revealed a group of 23 rare variants (frequencies ≤ 1%) associated with HDL-C (P = 0.0478). Haplotype analysis identified four SCARB1 regions associated with HDL-C (global P < 0.05). CONCLUSIONS: To our knowledge, this is the first report of a comprehensive association study of SCARB1 variations with lipid traits in an African Black population. Our results showed the consistent association of SCARB1 variants with HDL-C across various association analyses, supporting the role of SCARB1 in lipoprotein-lipid regulatory mechanism.


Assuntos
Estudos de Associação Genética/métodos , Variação Genética , Lipídeos/sangue , Receptores Depuradores Classe B/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Apolipoproteína A-I/sangue , HDL-Colesterol/sangue , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Nigéria , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Adulto Jovem
14.
Anal Bioanal Chem ; 407(26): 8121-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26345440

RESUMO

Quantification of human hemoglobin (Hb) is essential for diagnosis of anemia, especially for screening for thalassemia and sickle cell disease. The main methods currently used for quantification of Hb, including spectrophotometry, fluorimetry, and electrochemical assays, are all based on the structural integrity of Hb, which could be affected by hemolysis and degradation. When used for disease screening, whole blood specimens cannot meet requirements for sample collecting, transport, and storage. Here, we report a novel MS-MS method for quantification of Hb from dried blood spots (DBS) by use of a triple-quadrupole mass spectrometer. Proteospecific peptides from α-globin chains were selected after tryptic digestion. The precursor → product ion transitions of representative peptides were studied to identify the best choice with regard to sensitivity and chromatographic properties. For quantification, stable isotope-labeled peptides were used as internal standards. The concentration of Hb in each sample was obtained by calculation on the basis of established equations. The precision of the method was within 15 % and accuracy was in the range -7 to 13.0 %. Compared with routine clinical results obtained by use of the automated hematology analyzer (AHA) assay, the correlation, r (2), was >0.993. When used for determination of anemia levels the sensitivity of the assay was 95.7 % and specificity 96.5 %. Our new approach for quantification of the concentration of Hb from DBS is feasible, and precision is acceptable. The method could be used for determination of anemia levels when screening for hemoglobin disorders. Graphical Abstract Quantification of human hemoglobin from digested dried blood spot samples using tandem mass spectrometry.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Hemoglobinas/análise , Espectrometria de Massas em Tandem/métodos , Adulto , Sequência de Aminoácidos , Criança , Feminino , Humanos , Recém-Nascido , Limite de Detecção , Masculino , Dados de Sequência Molecular
15.
Mol Neuropsychiatry ; 1(1): 1-12, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26213687

RESUMO

Genome-wide expression and genotyping technologies have uncovered the genetic bases of complex diseases at unprecedented rates; However despite its heavy burden and high prevalence, the molecular characterization of major depressive disorder (MDD) has lagged behind. Transcriptome studies report multiple brain disturbances but are limited by small sample sizes. Genome-wide association studies (GWAS) report weak results but suggest overlapping genetic risk with other neuropsychiatric disorders. We performed systematic molecular characterization of altered brain function in MDD, using meta-analysis of differential expression in eight gene array studies in three corticolimbic brain regions in 101 subjects. The identified "metaA-MDD" genes suggest altered neurotrophic support, brain plasticity and neuronal signaling in MDD. Notably, metaA-MDD genes display low connectivity and hubness in coexpression networks, and uniform genomic distribution, consistent with diffuse polygenic mechanisms. We next integrated these findings with results from over 1800 published GWAS and show that genetic variations nearby metaA-MDD genes predict greater risk for neuropsychiatric disorders and notably for age-related phenotypes, but not for other medical illnesses, including those frequently co-morbid with depression, or body characteristics. Collectively, the intersection of unbiased investigations of gene function (transcriptome) and structure (GWAS) provides novel leads to investigate molecular mechanisms of MDD and suggest common biological pathways between depression, other neuropsychiatric diseases, and brain aging.

16.
Neurobiol Aging ; 36(8): 2443.e21-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26058841

RESUMO

Over 20 risk loci have been identified for late-onset Alzheimer's disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here, we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (odds ratio = 7.40, p = 3.66E-06). In addition to Alzheimer's disease risk, we also examined the association of R47H with Alzheimer's disease-related phenotypes, including age-at-onset, psychosis, and amyloid deposition but found no significant association. Our results corroborate those of other studies implicating TREM2 as an LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration.


Assuntos
Doença de Alzheimer/genética , Estudos de Associação Genética , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Receptores Imunológicos/genética , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Grupo com Ancestrais do Continente Europeu , Feminino , Heterozigoto , Humanos , Masculino , Fenótipo , Risco
18.
Biomed Res Int ; 2015: 587465, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25883965

RESUMO

Genetic variation in lipid regulatory genes, particularly APOE, significantly influences the risk of coronary artery disease (CAD). This study aimed to assess the association between APOE polymorphism and angiographically assessed coronary stenosis in Pakistani population. A total of 695 subjects (22.3% female, mean age = 54 ± 11 years) presenting with chest pain were enrolled after obtaining written informed consent. CAD stenosis/extent was assessed by angiography. Patients were classified as having severe stenosis (≥ 70%), moderate stenosis (30-69%), and mild stenosis (<30%). CAD patients with ≥ 70% stenosis (n = 491) were further categorized based on possessing one, two, or three vessel diseases to assess the disease extent. Genomic DNA from leukocytes was isolated with DNA purification kit (Qiagen) and APOE polymorphisms (E2/E3/E4) were determined using TaqMan assays. Six hundred and seventy-two of 695 subjects were successfully genotyped. The frequency of APOE∗4 carriers (3/4 and 4/4 genotypes) was significantly higher in severe stenosis group (≥ 70%) as compared to mild group (<30%) (22.8% versus 13.01%; P = 0.01). In multiple regression, the odds ratio for APOE∗4 carriers to develop ≥ 70% stenosis was 2.16 (95% CI: 1.29-3.79; P < 0.005). In conclusion, the presence of APOE∗4 allele is a significant risk factor to develop severe coronary stenosis (>70%) among Pakistanis.


Assuntos
Alelos , Apolipoproteínas E/genética , Estenose Coronária/genética , Polimorfismo Genético , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Fatores de Risco
19.
Immunogenetics ; 67(5-6): 277-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25904084

RESUMO

Rheumatoid arthritis (RA) and type 1 diabetes (T1D) are two autoimmune disorders that have been reported to co-occur in the same subjects or in different subjects from the same family. This suggests the sharing of disease susceptibility loci between RA and T1D. This study was aimed to find out such susceptibility loci that are common in both T1D and RA in Pakistani population. A total of 366 Pakistanis comprising related and unrelated RA cases and controls were recruited. Blood samples were collected from all patients followed by DNA isolation. Thirty-one single-nucleotide polymorphisms (SNPs) previously reported to be associated with T1D were genotyped in RA cases and controls using TaqMan SNP genotyping assays. Data was analyzed using FamCC software. We have identified seven SNP associations that survived multiple testing corrections using false discovery rate: SKAP2/rs7804356 (p = 2.47E-04), GLIS3/rs7020673 (p = 2.86E-04), GSDMB/rs2290400 (p = 23.48E-04), BACH2/rs11755527 (p = 9.16E-04), C6orf173/ rs9388489 (p = 3.11E-03), PRKCQ/DKFZp667F0711/ rs947474 (p = 4.53E-03), and DLK1/ rs941576 (p = 9.51E-03). Our results support the presence of overlapping loci between RA and T1D in Pakistani patients.


Assuntos
Artrite Reumatoide/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Adulto , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Polimorfismo de Nucleotídeo Único
20.
J Alzheimers Dis ; 45(2): 651-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25649651

RESUMO

There is a strong genetic basis for late-onset of Alzheimer's disease (LOAD), and thus far >20 genes/loci have been identified that affect the risk of LOAD. In addition to disease risk, genetic variation at these loci may also affect components of the natural history of AD, such as survival in AD. In this study, we first examined the role of known LOAD genes with survival time in 983 AD patients. We then performed genome-wide single-nucleotide polymorphism (SNP) and gene-based association analyses to identify novel loci that may influence survival of AD. Survival analysis was conducted using Cox proportional hazards regression under an additive genetics model. We found multiple nominally significant associations (p < 0.01) either within or adjacent to known LOAD genes. Genome-wide SNP analysis identified multiple suggestive novel loci and two of them were also significant in gene-based analysis (CCDC85C and NARS2) that survived after controlling for false-discovery rate at 0.05. In summary, we have identified two novel genes for survival in AD that need to be replicated in independent samples. Our findings highlight the importance of focusing on AD-related phenotypes that may help to identify additional genes relevant toAD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Doença de Alzheimer/mortalidade , Aspartato-tRNA Ligase/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Modelos de Riscos Proporcionais
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