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Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with the major symptoms comprising loss of movement coordination (motor dysfunction) and non-motor dysfunction, including gastrointestinal symptoms. Alterations in the gut microbiota composition have been reported in PD patients vs. controls. However, it is still unclear how these compositional changes contribute to disease etiology and progression. Furthermore, most of the available studies have focused on European, Asian, and North American cohorts, but the microbiomes of PD patients in Latin America have not been characterized. To address this problem, we obtained fecal samples from Colombian participants (n = 25 controls, n = 25 PD idiopathic cases) to characterize the taxonomical community changes during disease via 16S rRNA gene sequencing. An analysis of differential composition, diversity, and personalized computational modeling was carried out, given the fecal bacterial composition and diet of each participant. We found three metabolites that differed in dietary habits between PD patients and controls: carbohydrates, trans fatty acids, and potassium. We identified six genera that changed significantly in their relative abundance between PD patients and controls, belonging to the families Lachnospiraceae, Lactobacillaceae, Verrucomicrobioaceae, Peptostreptococcaceae, and Streptococcaceae. Furthermore, personalized metabolic modeling of the gut microbiome revealed changes in the predicted production of seven metabolites (Indole, tryptophan, fructose, phenylacetic acid, myristic acid, 3-Methyl-2-oxovaleric acid, and N-Acetylneuraminic acid). These metabolites are associated with the metabolism of aromatic amino acids and their consumption in the diet. Therefore, this research suggests that each individual's diet and intestinal composition could affect host metabolism. Furthermore, these findings open the door to the study of microbiome-host interactions and allow us to contribute to personalized medicine.
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BACKGROUND: The Apolipoprotein E (APOE) gene is the main risk factor for late-onset Alzheimer disease (LOAD). Genetic variants and haplotypes in regions near the APOE locus may be associated with LOAD in the Colombian population. OBJECTIVE: We evaluated frequencies and risk of genetic variants and haplotypes in APOE, TOMM40, and APOC1 promoters, also in putative regulatory enhancer elements (TOMM40 IVS2-4 and TOMM40 IVS6), and in cis-regulatory elements (ME1 and BCR). MATERIALS AND METHODS: Our case-control association study was carried out in 50 patients with LOAD and 50 controls. We determined frequencies and odd ratios for genetic variants and haplotypes. RESULTS: We found a significant association between LOAD and genetic variants at the TOMM40 promoter, at TOMM40 IVS2-4 and TOMM40 IVS6 regulatory enhancer elements, and at the APOC1 promoter. Particularly, variants of Poly-T and APOC1 promoter could anticipate the age of onset of LOAD in our population. We identified three risk haplotypes in TOMM40 (ACGGAG, ACGGGG, and ATAGGC) related to LOAD's age of onset. We also found other risk or protection haplotypes at the TOMM40 and APOE promoters, at TOMM40 IVS2-4, TOMM40 IVS6 regulatory enhancer elements, and at ME1. CONCLUSION: Genetic variants and haplotypes near the APOE locus are related to LOAD risk and accelerated onset of LOAD in the Colombian population.
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Doença de Alzheimer , Apolipoproteína C-I , Apolipoproteínas E , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Idade de Início , Apolipoproteína C-I/genética , Apolipoproteínas E/genética , Colômbia/epidemiologia , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/genéticaRESUMO
In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the -13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the -13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of -13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the -13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the -13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the -13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.
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OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.
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Loci Gênicos/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Hispânico ou Latino/genética , Doença de Parkinson/etnologia , Doença de Parkinson/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Polimorfismo de Nucleotídeo Único/genética , América do Sul/etnologiaRESUMO
OBJECTIVE: To investigate the differences in the epigenomic patterns of DNA methylation in peripheral leukocytes between patients with periodontitis and gingivally healthy controls evaluating its functional meaning by functional enrichment analysis. BACKGROUND: The DNA methylation profiling of peripheral leukocytes as immune-related tissue potentially relevant as a source of biomarkers between periodontitis patients and gingivally healthy subjects has not been investigated. METHODS: A DNA methylation epigenome-wide study of peripheral leukocytes was conducted using the Illumina MethylationEPIC platform in sixteen subjects, eight diagnosed with periodontitis patients and eight age-matched and sex-matched periodontally healthy controls. A trained periodontist performed the clinical evaluation. Global DNA methylation was estimated using methylation-sensitive high-resolution melting in LINE1. Routine cell count cytometry and metabolic laboratory tests were also performed. The analysis of differentially methylated positions (DMPs) and differentially methylated regions (DMRs) was made using R/Bioconductor environment considering leukocyte populations assessed in both routine cell counts and using the FlowSorted.Blood.EPIC package. Finally, a DMP and DMR intersection analysis was performed. Functional enrichment analysis was carried out with the differentially methylated genes found in DMP. RESULTS: DMP analysis identified 81 differentially hypermethylated genes and 21 differentially hypomethylated genes. Importantly, the intersection analysis showed that zinc finger protein 718 (ZNF718) and homeobox A4 (HOXA4) were differentially hypermethylated and zinc finger protein 57 (ZFP57) was differentially hypomethylated in periodontitis. The functional enrichment analysis found clearly immune-related ontologies such as "detection of bacterium" and "antigen processing and presentation." CONCLUSION: The results of this study propose three new periodontitis-related genes: ZNF718, HOXA4, and ZFP57 but also evidence the suitability and relevance of studying leukocytes' DNA methylome for biological interpretation of systemic immune-related epigenetic patterns in periodontitis.
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Metilação de DNA , Periodontite , Metilação de DNA/genética , Epigenoma , Genes Homeobox , Proteínas de Homeodomínio , Humanos , Projetos Piloto , Fatores de TranscriçãoRESUMO
Recently, mutations in the RNA polymerase III subunit A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A has important roles in transcription regulation of small RNAs, including tRNA, 5S rRNA, and 7SK rRNA. We aim to describe the cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control patient were cultured in vitro. The mutation caused a decrease in the expression of wildtype POLR3A mRNA and POLR3A protein and a sharp increase in mutant protein expression. In addition, there was an increase in the nuclear localization of the mutant protein. These changes were associated with an increase in the number and area of nucleoli and to a high increase in the expression of pP53 and pH2AX. All these changes were associated with premature senescence. The present observations add to our understanding of the differences between Hutchinson-Gilford progeria syndrome and WRS and opens new alternatives to study cell senesce and human aging.
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Retardo do Crescimento Fetal , Fibroblastos , Progéria , RNA Polimerase III , Proteína Supressora de Tumor p53/metabolismo , Nucléolo Celular/fisiologia , Células Cultivadas , Senescência Celular/fisiologia , Dano ao DNA , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Fibroblastos/fisiologia , Fibroblastos/ultraestrutura , Expressão Gênica , Humanos , Mutação , Progéria/genética , Progéria/patologia , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , RNA Ribossômico 5S/metabolismoRESUMO
BACKGROUND: Dementia of the Alzheimer's type (DAT) impacts Hispanics disproportionately, with almost a twofold elevated risk of developing DAT, as well as earlier onset of the disease, than in non-Hispanic Whites. However, the role of main risk factors for DAT, such as APOE-É4 and blood pressure (BP) levels, remains uncertain among Hispanics. OBJECTIVE: To investigate the association of APOE-É4 and BP levels, measures with 24-h ambulatory BP monitoring, with incidence of DAT in an elderly cohort of Hispanics. METHODS: 1,320 participants from the Maracaibo Aging Study, free of dementia at the baseline, and with ambulatory BP measurements and APOE genotype available were included. Adjusted Cox proportional models were performed to examine 1) the incidence of DAT and 2) the relationship between BP levels and DAT according to APOE genotypes. Models were adjusted by competing risk of death before the onset of DAT. Model performance was assessed by likelihood test. RESULTS: The average follow-up time was 5.3 years. DAT incidence was 5.8 per 1000 person-year. APOE-É4 carriers had a higher risk of DAT. In unadjusted analyses, conventional, 24-h, and nighttime systolic BP levels were significantly higher in participants who developed DAT and of APOE-É4 carriers (p < 0.05). After adjustment for competing risks, only higher nighttime systolic BP was associated with DAT incidence, but only among subjects carrying APOE-É4. CONCLUSION: In this Hispanic population, both APOE-É4 genotype and assessment of nocturnal systolic BP (rather than diurnal or office BP) were necessary to estimate DAT risk.
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Doença de Alzheimer/genética , Apolipoproteína E4/genética , Pressão Sanguínea/genética , Ritmo Circadiano/genética , Demência/genética , Genótipo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/etnologia , Demência/diagnóstico , Demência/etnologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Venezuela/etnologiaRESUMO
Introduction: The HapMap and the 1000 Genomes projects have been important for understanding the genetic component of common diseases and normal phenotypes. However, the Colombian genetic variability included in these projects is not fully representative of our country. Objective: To contribute to the knowledge of the Colombian genetic variability through the genomic study of a sample of individuals from Bogotá. Materials and methods: A total of 2,372,784 genetic markers were genotyped in 32 individuals born in Bogotá whose parents are from the same region, using the Illumina™ platform. The genetic variability levels were determined and compared with the data available from other populations of the 1000 Genomes Project. Results: The genetic variability detected in the individuals from Bogotá was similar to those with shared ancestry. However, despite the low levels of genetic differentiation between Bogotá and Medellín, populations the principal component analysis suggested a different genetic composition in them. Conclusions: Our genomic analysis of a Bogotá sample allowed us to detect similarities and differences with other American populations. The increase of the Bogotá sample and the inclusion of samples from other regions of the country will improve our understanding of the genetic variability in Colombia, essential for studies of human health and the prevention and treatment of common diseases in our country.
Introducción. Los proyectos del mapa de haplotipos (HapMap) y de los 1.000 genomas han sido fundamentales para la compresión del componente genético de las enfermedades comunes y los fenotipos normales. Sin embargo, la variabilidad genética colombiana incluida en estos proyectos no es representativa del país. Objetivo. Contribuir al conocimiento de la variabilidad genética de la población colombiana a partir del estudio genómico de una muestra de individuos de Bogotá. Materiales y métodos. Se genotipificaron 2'372.784 marcadores genéticos de 32 individuos nacidos en Bogotá y de padres originarios de la misma ciudad utilizando la plataforma Illumina™. Los niveles de variabilidad genética se determinaron y se compararon con los datos disponibles de otras poblaciones del proyecto de los 1.000 genomas. Resultados. Los individuos analizados presentaron una variabilidad genética semejante a la de poblaciones con las que comparten ancestros. No obstante, a pesar de la poca diferenciación genética detectada en la población de Bogotá y en la de Medellín, el análisis de los componentes principales sugiere una composición genética diferente en las dos poblaciones. Conclusiones. El análisis genómico de la muestra de Bogotá permitió detectar similitudes y diferencias con otras poblaciones americanas. El aumento de tamaño de la muestra bogotana y la inclusión de muestras de otras regiones del país permitirán una mejor compresión de la variabilidad genética en Colombia, lo cual es fundamental para los estudios de salud humana, y la prevención y el tratamiento de enfermedades comunes en el país.
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Marcadores Genéticos , Variação Genética , Haplótipos , Indígena Americano ou Nativo do Alasca/genética , Povo Asiático/genética , População Negra/genética , Cidades/etnologia , Colômbia/etnologia , Feminino , Projeto Genoma Humano , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
Resumen Introducción. Los proyectos del mapa de haplotipos (HapMap) y de los 1.000 genomas han sido fundamentales para la compresión del componente genético de las enfermedades comunes y los fenotipos normales. Sin embargo, la variabilidad genética colombiana incluida en estos proyectos no es representativa del país. Objetivo. Contribuir al conocimiento de la variabilidad genética de la población colombiana a partir del estudio genómico de una muestra de individuos de Bogotá. Materiales y métodos. Se genotipificaron 2'372.784 marcadores genéticos de 32 individuos nacidos en Bogotá y de padres originarios de la misma ciudad utilizando la plataforma Illumina™. Los niveles de variabilidad genética se determinaron y se compararon con los datos disponibles de otras poblaciones del proyecto de los 1.000 genomas. Resultados. Los individuos analizados presentaron una variabilidad genética semejante a la de poblaciones con las que comparten ancestros. No obstante, a pesar de la poca diferenciación genética detectada en la población de Bogotá y en la de Medellín, el análisis de los componentes principales sugiere una composición genética diferente en las dos poblaciones. Conclusiones. El análisis genómico de la muestra de Bogotá permitió detectar similitudes y diferencias con otras poblaciones americanas. El aumento de tamaño de la muestra bogotana y la inclusión de muestras de otras regiones del país permitirán una mejor compresión de la variabilidad genética en Colombia, lo cual es fundamental para los estudios de salud humana, y la prevención y el tratamiento de enfermedades comunes en el país.
Abstract Introduction: The HapMap and the 1000 Genomes projects have been important for understanding the genetic component of common diseases and normal phenotypes. However, the Colombian genetic variability included in these projects is not fully representative of our country. Objective: To contribute to the knowledge of the Colombian genetic variability through the genomic study of a sample of individuals from Bogotá. Materials and methods: A total of 2,372,784 genetic markers were genotyped in 32 individuals born in Bogotá whose parents are from the same region, using the Illumina™ platform. The genetic variability levels were determined and compared with the data available from other populations of the 1000 Genomes Project. Results: The genetic variability detected in the individuals from Bogotá was similar to those with shared ancestry. However, despite the low levels of genetic differentiation between Bogotá and Medellín, populations the principal component analysis suggested a different genetic composition in them. Conclusions: Our genomic analysis of a Bogotá sample allowed us to detect similarities and differences with other American populations. The increase of the Bogotá sample and the inclusion of samples from other regions of the country will improve our understanding of the genetic variability in Colombia, essential for studies of human health and the prevention and treatment of common diseases in our country.
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Feminino , Humanos , Masculino , Variação Genética , Haplótipos , Marcadores Genéticos , Projeto Genoma Humano , Cidades/etnologia , Colômbia/etnologia , Polimorfismo de Nucleotídeo Único , População Negra/genética , Indígena Americano ou Nativo do Alasca/genética , Povo Asiático/genética , População Branca/genéticaRESUMO
INTRODUCTION: Late-onset Alzheimer disease (LOAD) is the most common dementia worldwide. APOE-[Latin Small Letter Open E]4 and BIN1 (Bridging Integrator 1) have been implicated in the pathogenesis of this disease, but, although DNA methylation of dinucleotide CpGs in the BIN1 gene influences alterations, it has not been studied in Hispanics. OBJECTIVE: The objective of this study was to evaluate the BIN1 3' intergenic region DNA methylation patterns in a Colombian sample of LOAD patients. METHODS: A case-control study was conducted in 50 individuals with LOAD and 50 age-sex matched controls to determine associations of LOAD with DNA methylation. DNA was isolated from peripheral blood, and methylation levels of 8 CpGs were estimated by bisulfite conversion followed by Sanger sequencing with direct PCR analysis. Logistic regression models adjusted by age, sex, and APOE were used to calculate risk associations between methylation levels and LOAD. RESULTS: Overall, participants with LOAD had significantly lower methylation levels on CpG26 (0.86±0.11 vs. 0.95±0.05; P>0.001), CpG44 (0.84±0.09 vs. 0.94±0.06; P=0.001), and CpG87 (0.64±0.12 vs. 0.82±0.10; P>0.001). Adjusted regression models showed that decreased methylation levels of these CpGs remained as risk factors for LOAD (P<0.05). CONCLUSIONS: Hypomethylation of CpGs in BIN1 might play an important role in the expression of BIN1 and may be a biomarker for identifying individuals at high risk of developing LOAD.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Metilação de DNA/genética , Fosfatos de Dinucleosídeos/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Idoso , Apolipoproteína E4/genética , Estudos de Casos e Controles , Colômbia , Fosfatos de Dinucleosídeos/sangue , Feminino , Humanos , Transtornos de Início Tardio/genética , MasculinoRESUMO
BACKGROUND: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the APOE gene and apolipoprotein E (ApoE) plasma levels as MCI biomarkers in Colombian subjects with MCI and controls. METHODS: In total, 100 participants were included (71% women; average age, 70 years; range, 43â»91 years). MCI was diagnosed by neuropsychological testing, medical and social history, activities of daily living, cognitive symptoms and neuroimaging. Using multivariate logistic regression models adjusted by age and gender, we examined the risk association of MCI with plasma ApoE and APOE methylation. RESULTS: MCI was diagnosed in 41 subjects (average age, 66.5 ± 9.6 years) and compared with 59 controls. Elevated plasma ApoE and APOE methylation of CpGs 165, 190, and 198 were risk factors for MCI (p < 0.05). Higher CpG-227 methylation correlated with lower risk for MCI (p = 0.002). Only CpG-227 was significantly correlated with plasma ApoE levels (correlation coefficient = -0.665; p = 0.008). CONCLUSION: Differential APOE methylation and increased plasma ApoE levels were correlated with MCI. These epigenetic patterns require confirmation in larger samples but could potentially be used as biomarkers to identify early stages of MCI.
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Apolipoproteínas E/genética , Disfunção Cognitiva/genética , Metilação de DNA/genética , Éxons/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/sangue , Disfunção Cognitiva/sangue , Ilhas de CpG/genética , Feminino , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
OBJECTIVE: To study DNA methylation patterns of cortical pyramidal layers susceptible to late-onset Alzheimer's disease (LOAD) neurodegeneration. METHODS: Laser-assisted microdissection to select pyramidal layers' cells in frontal cortex of 32 human brains (18 LOAD) and Infinium DNA Methylation 450K analysis were performed to find differential methylated positions and regions, in addition to the corresponding gene set functional enrichment analyses. RESULTS: Differential hypermethylation in several genomic regions and genes mainly in HOXA3, GSTP1, CXXC1-3 and BIN1. The functional enrichment analysis revealed genes significantly related to oxidative-stress and synapsis. CONCLUSION: The present results indicate the differentially methylated genes related to neural projections, synapsis, oxidative stress and epigenetic regulator genes and represent the first epigenome of cortical pyramidal layers in LOAD.
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Doença de Alzheimer/genética , Metilação de DNA , Lobo Frontal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Feminino , Glutationa S-Transferase pi/genética , Proteínas de Homeodomínio/genética , Humanos , Microdissecção e Captura a Laser , Masculino , Proteínas Nucleares/genética , Estresse Oxidativo , Células Piramidais/metabolismo , Transmissão Sináptica , Transativadores , Proteínas Supressoras de Tumor/genéticaRESUMO
OBJECTIVE: We evaluated the association of several single-nucleotide polymorphisms in the triggering receptor expressed on myeloid cells 2 (TREM2) gene in a Colombian sample of late-onset Alzheimer disease (LOAD). METHODS: The p.Q33* (rs104894002), p.R47H (rs75932628), p.R62H (rs143332484), and p.D87N (rs142232675) variants of TREM2 gene were directly genotyped using KASPar technology in 358 cases and 329 healthy controls. Sanger sequencing was used to validate >10% of KASPar's results. The Fisher exact test was used to compare the distribution of allelic and genotype frequency between cases and controls, and the Bonferroni correction was set at P<0.05. RESULTS: The minor allele frequency of rs75932628-T was 0.009 in cases and was not found in any healthy controls which suggests a significant association between rs75932628-T and LOAD risk in our sample (P=0.010). The rs143332484-T variant did not exhibit a significant association (P=0.160), whereas rs104894002 and rs142232675 were not found. CONCLUSIONS: Our findings suggest that the rs75932628-T variant of TREM2 is an important risk factor for LOAD in the Colombian population.
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Doença de Alzheimer/genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Colômbia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
INTRODUCTION: Cognitive disorders are a clinical and research challenge; in particular, the mild cognitive disorder (MiCD) requires diagnostic suspicion and tools with adequate performance for its detection. The objective of this study was the validation of a short cognitive test (CATest) for the detection of MiCD in population of 50 years or more. METHODS: A diagnostic accuracy study was assembled and performed in a prospective cohort. A consecutive sample of 200 Colombian subjects who represented the whole spectrum of the condition of interest allowed us to reach the objective. Validity was determined by concurrent criteria. The cut points were determined by the ROC curves considering the best overall performance and accuracy of the test. RESULTS: CATest was validated to detection of MiCD at a cut-off point of 18. As a result, scores lower than 18 classified the participants as MiCD. At this cut-off point, CATest showed sensitivity of 84.3% (CI 76 to 90.16), specificity of 71.4% (CI 95% 61.8 to 79.43), positive predictive value of 75% ( 95% CI 66.79 to 82.42), and area under curve AUC 0.8518 (standard error SE 0.0265). DISCUSSION: CATest has an adequate performance as a short cognitive test for the detection of MiCD. Its performance is superior to MiniMental and similar to Montreal Cognitive test (MoCA) according to the data reported in the literature. The advantages over other tests are the evaluation of all cognitive domains, time of application, and easy interpretation of results. CATest is a free use alternative for MiCD detection.
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Resumen Introducción: El trastorno por déficit de atención e hiperactividad (TDAH) es una perturbación con elevada prevalencia en población infantil de Bogotá. Entre las causas de este trastorno se encuentran factores genéticos y ambientales, pero pocos estudios han tratado de abordar el componente genético en población colombiana. Objetivos: Realizar un estudio de asociación genética entre diferentes polimorfismos y el TDAH en la población de Bogotá. Métodos: Múltiples polimorfismos de los genes DAT1, SERT, COMT y BDNF fueron genotipificados empleando las técnicas de PCR convencional y RFLP en 97 tríos de Bogotá. El test de desequilibrio de trasmisión (TDT) se empleó para determinar la asociación entre las diferentes variantes y el TDAH. Resultados: El análisis de TDT no identificó una transmisión preferencial de alelos de ninguna de las variantes estudiadas. Conclusiones: Nuestros resultados indican que la etiología del TDAH es heterogénea e involucra diversos factores genéticos. Futuros estudios enfocados en otros polimorfismos candidatos en una muestra más grande ayudarán a comprender el TDAH en la población colombiana.
Abstract Background: Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. Objectives: To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. Methods: We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. Results: The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. Conclusions: Our results suggest that the etiology of the ADHD maybe complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population.
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Humanos , Masculino , Criança , Transtorno do Deficit de Atenção com Hiperatividade , Genética , Jogos e Brinquedos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Colômbia , Fator Neurotrófico Derivado do Encéfalo , Conhecimento , GenesRESUMO
BACKGROUND: Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. OBJECTIVES: To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. METHODS: We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. RESULTS: The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. CONCLUSIONS: Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Criança , Colômbia , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de RestriçãoRESUMO
OBJECTIVE: We evaluated the association of several single-nucleotide polymorphisms in different genes including APOE, TOMM40, CR1, PVRL2, SORL1, PICALM, and GWA_14q32.13 in a Colombian sample of Late-Onset Alzheimer disease (LOAD) patients. METHODS: A case-control study was conducted in 362 individuals (181 LOADs and 181 controls) to determine the association of single-nucleotide polymorphisms in APOE (e2, e3, and e4), TOMM40 (rs2075650), CR1 (rs665640), PVRL2 (rs6859), SORL1 (rs11218304), PICALM (rs3851179), and GWA_14q32.13 (rs11622883) with LOAD in a sample from Colombia. RESULTS: We were able to confirm the previously reported association of the APOE4 allele with AD. In addition, we report a new significant association with rs2075650 of TOMM40 for LOAD in our sample. We did not detect any significant interaction between TOMM40 and APOE4 carriers (heterozygous or homozygous) for disease risk development. However, Kaplan-Meier survival analyses suggest that AD patients with TOMM40 allele rs2075650-G have an average age of disease onset of 6 years earlier compared with carriers of the A allele. In addition, the age of disease onset is earlier if APOE4/4 is present. CONCLUSION: Our findings suggest that rs2075650 of TOMM40 could be involved in earlier presentation of LOAD in the Colombian population.
Assuntos
Doença de Alzheimer/genética , Proteínas de Membrana Transportadoras/genética , Nectinas/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Complemento 3b/genética , Idoso , Alelos , Apolipoproteína E4/genética , Estudos de Casos e Controles , Colômbia , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Proteínas do Complexo de Importação de Proteína Precursora MitocondrialRESUMO
INTRODUCTION: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson´s disease, but the prevalence of these mutations varies among populations. OBJECTIVE: to analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055 G>A transition) in a sample of Colombian patients. METHODS: In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls. RESULTS: Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson´s signs, and one completely asymptomatic control (1/162, 0.6%). CONCLUSION: The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.
INTRODUCCIÓN: Mutaciones en el LRRK2 (del inglés gen leucine-rich repeat kinase 2) o Dardarina se consideran una causa común de enfermedad de Parkinson autosómica dominante. Sin embargo, la prevalencia de estas mutaciones varia en diferentes poblaciones. OBJETIVO: analizar la frecuencia de la mutación p.G2019S (transición c.6055 G>A) del gen LRRK2en una muestra de pacientes colombianos. MÉTODOS: En el presente estudio analizamos la frecuencia de la mutación en 154 pacientes con enfermedad de Parkinson familiar o esporádica, y 162 controles normales. RESULTADOS: se determinó la presencia de la mutación en 2 casos de Parkinson (2/154, 1.3%) los cuales presentan los signos clásicos de la enfermedad y en un control completamente asintomático (1/162, 0.6%). CONCLUSIÓN: La mutación p.G2019S no es un factor causal importante de la Enfermedad de Parkinson en la población Colombiana, y muestra frecuencias similares a las reportadas en otras poblaciones latinoamericanas.
Assuntos
Frequência do Gene , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Colômbia , Feminino , Predisposição Genética para Doença , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/fisiopatologiaRESUMO
Introduction: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson's disease, but the prevalence of these mutations varies among populations. Objective: To analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055G>A transition) in a sample of Colombian patients. Methods: In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls. Results: Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson's signs, and one completely asymptomatic control (1/162, 0.6%). Conclusion: The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations.
Introducción: Las mutaciones en el LRRK2 (del inglés gen leucinerich repeat kinase 2) o Dardarina se consideran una causa común de enfermedad de Parkinson autosómica dominante. Sin embargo, la prevalencia de estas mutaciones varia en diferentes poblaciones. Objetivo: Snalizar la frecuencia de la mutación p.G2019S (transición c.6055 G>A) del gen LRRK2en una muestra de pacientes colombianos. Métodos: En el presente estudio analizamos la frecuencia de la mutación en 154 pacientes con enfermedad de Parkinson familiar o esporádica, y 162 controles normales. Resultados: Se determinó la presencia de la mutación en 2 casos de Parkinson (2/154, 1.3%) los cuales presentan los signos clásicos de la enfermedad y en un control completamente asintomático (1/162, 0.6%). Conclusión: La mutación p.G2019S no es un factor causal importante de la Enfermedad de Parkinson en la población Colombiana, y muestra frecuencias similares a las reportadas en otras poblaciones latinoamericanas.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Frequência do Gene , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Idade de Início , Estudos de Casos e Controles , Colômbia , Predisposição Genética para Doença , Mutação , Doença de Parkinson/fisiopatologiaRESUMO
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder. It is characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Early-onset familial forms of PD are associated with mutations in several genes, including parkin, pink1 and dj-1. DJ-1 encodes a protein whose neuroprotective function has not been completely clarified yet. We aim to understand the neuroprotective mechanisms of DJ-1, in particular, DJ-1's involvement in the regulation of the PI3K/PTEN/AKT/mTOR pathway and neuronal autophagy in a neurotoxic context induced by C2-ceramide, by using CAD cells, a murine cathecolaminergic cell line. We demonstrated that C2-ceramide induces CAD cell death associated with decreased phosphorylation of PTEN at Ser380, AKT at Ser473, and mTOR at Ser2448; and increased of autophagic flux (increased LC3-II and autophagosome formation). Additionally, we showed that overexpression of DJ-1 protects against C2-ceramide-induced neuronal death and it is not associated with change in the phosphorylation of mTOR at Ser2448. In conclusion, these data suggest that DJ-1 reinforces the PI3K/AKT survival pathway and inhibits autophagy, probably by a mechanism independent from mTOR.