RESUMO
BACKGROUND: Cognitive functions represent useful endophenotypes to identify the association between genetic variants and schizophrenia. In this sense, the NR4A2 gene has been implicated in schizophrenia and cognition in different animal models and clinical trials. We hypothesized that the NR4A2 gene is associated with working memory performance in schizophrenia. This study aimed to analyze two variants and the expression levels of the NR4A2 gene with susceptibility to schizophrenia, as well as to evaluate whether possession of NR4A2 variants influence the possible correlation between gene expression and working memory performance in schizophrenia. METHODS: The current study included 187 schizophrenia patients and 227 controls genotyped for two of the most studied NR4A2 genetic variants in neurological and neuropsychiatric diseases. Genotyping was performed using High Resolution Melt and sequencing techniques. In addition, mRNA expression of NR4A2 was performed in peripheral mononuclear cells of 112 patients and 118 controls. A group of these participants, 54 patients and 87 controls, performed the working memory index of the WAIS III test. RESULTS: Both genotypic frequencies of the two variants and expression levels of the NR4A2 gene showed no significant difference when in patients versus controls. However, patients homozygous for the rs34884856 promoter variant showed a positive correlation between expression levels and auditory working memory. CONCLUSIONS: Our finding suggested that changes in expression levels of the NR4A2 gene could be associated with working memory in schizophrenia depending on patients' genotype in a sample from a Mexican population.
Assuntos
Esquizofrenia , Estudos de Casos e Controles , Humanos , Transtornos da Memória , Memória de Curto Prazo , México , Testes Neuropsicológicos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Esquizofrenia/complicações , Esquizofrenia/genéticaRESUMO
Here we studied HLA blocks and haplotypes in a group of 218 Lacandon Maya Native American using a high-resolution next generation sequencing (NGS) method. We assessed the genetic diversity of HLA class I and class II in this population, and determined the most probable ancestry of Lacandon Maya HLA class I and class II haplotypes. Importantly, this Native American group showed a high degree of both HLA homozygosity and linkage disequilibrium across the HLA region and also lower class II HLA allelic diversity than most previously reported populations (including other Native American groups). Distinctive alleles present in the Lacandon population include HLA-A*24:14 and HLA-B*40:08. Furthermore, in Lacandons we observed a high frequency of haplotypes containing the allele HLA-DRB1*04:11, a relatively frequent allele in comparison with other neighboring indigenous groups. The specific demographic history of the Lacandon population including inbreeding, as well as pathogen selection, may have elevated the frequencies of a small number of HLA class II alleles and DNA blocks. To assess the possible role of different selective pressures in determining Native American HLA diversity, we evaluated the relationship between genetic diversity at HLA-A, HLA-B and HLA-DRB1 and pathogen richness for a global dataset and for Native American populations alone. In keeping with previous studies of such relationships we included distance from Africa as a covariate. After correction for multiple comparisons we did not find any significant relationship between pathogen diversity and HLA genetic diversity (as measured by polymorphism information content) in either our global dataset or the Native American subset of the dataset. We found the expected negative relationship between genetic diversity and distance from Africa in the global dataset, but no relationship between HLA genetic diversity and distance from Africa when Native American populations were considered alone.
Assuntos
Variação Genética , Genética Populacional , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Desequilíbrio de Ligação , Adolescente , Adulto , África , Alelos , Feminino , Frequência do Gene , Genótipo , Geografia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Homozigoto , Humanos , Masculino , México/etnologia , Pessoa de Meia-Idade , Análise de Componente Principal , Adulto Jovem , Indígena Americano ou Nativo do AlascaRESUMO
BACKGROUND: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke. OBJECTIVE: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke. METHODS: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum. RESULTS: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant. CONCLUSION: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.
INTRODUCCIÓN: La paraoxonasa-1 (PON1) sérica asociada a las HDL presenta dos polimorfismos comunes en las posiciones 192 y 55. Estos polimorfismos se consideran determinantes para la capacidad de las HDL de proteger a las LDL de su modificación oxidativa. En este contexto, el genotipo de PON1 se ha asociado con enfermedades cerebrovasculares, que incluyen el infarto cerebral. OBJETIVO: Determinar las frecuencias alélicas y genotípicas de PON1-L55M y PON1- Q192R, así como las actividades enzimáticas de PON1 en sujetos con y sin infarto cerebral aterotrombótico. MÉTODOS: Se incluyeron 28 personas con infarto cerebral aterotrombótico y 29 sin infarto. Las genotipificaciones se realizaron mediante PCR-RFLP y las fenotipificaciones mediante la medición de las actividades paraoxonasa y arilesterasa en suero. RESULTADOS: Para el polimorfismo Q192R, las frecuencias alélicas (Q/R) fueron 0.46/0.54 y 0.48/0.52 (p= 0.843) para el grupo control y el grupo con infarto, respectivamente. Mientras que para el polimorfismo L55M, las frecuencias alélicas (L/M) fueron 0.81/0.19 para el grupo control y 0.78/0.22 para el grupo con infarto (p= 0.610). Los niveles de actividad paraoxonasa no fueron significativamente diferentes entre los grupos control y con infarto (450 vs. 348 Ul/mL, p= 0.093). Mientras que los niveles de actividad arilesterasa fueron significativamente diferentes entre los grupos estudiados (90 vs. 70 Ul/mL, p= 0.001), sin embargo, al ajustarla por regresión lineal múltiple, dejo de ser significativa. CONCLUSIÓN: Los polimorfismos Q192R y L55M, y la actividad paraoxonasa de la PON1 no son factores de riesgo para el infarto cerebral aterotrombótico en este estudio.
Assuntos
Arildialquilfosfatase/genética , Isquemia Encefálica/genética , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Adulto , Idoso , Alelos , Isquemia Encefálica/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Lineares , Masculino , México , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Acidente Vascular Cerebral/patologiaRESUMO
Abstract Background: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke. Objective: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke. Methods: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum. Results: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant. Conclusion: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.
Resumen Introducción: La paraoxonasa-1 (PON1) sérica asociada a las HDL presenta dos polimorfismos comunes en las posiciones 192 y 55. Estos polimorfismos se consideran determinantes para la capacidad de las HDL de proteger a las LDL de su modificación oxidativa. En este contexto, el genotipo de PON1 se ha asociado con enfermedades cerebrovasculares, que incluyen el infarto cerebral. Objetivo: Determinar las frecuencias alélicas y genotípicas de PON1-L55M y PON1- Q192R, así como las actividades enzimáticas de PON1 en sujetos con y sin infarto cerebral aterotrombótico. Métodos: Se incluyeron 28 personas con infarto cerebral aterotrombótico y 29 sin infarto. Las genotipificaciones se realizaron mediante PCR-RFLP y las fenotipificaciones mediante la medición de las actividades paraoxonasa y arilesterasa en suero. Resultados: Para el polimorfismo Q192R, las frecuencias alélicas (Q/R) fueron 0.46/0.54 y 0.48/0.52 (p= 0.843) para el grupo control y el grupo con infarto, respectivamente. Mientras que para el polimorfismo L55M, las frecuencias alélicas (L/M) fueron 0.81/0.19 para el grupo control y 0.78/0.22 para el grupo con infarto (p= 0.610). Los niveles de actividad paraoxonasa no fueron significativamente diferentes entre los grupos control y con infarto (450 vs. 348 Ul/mL, p= 0.093). Mientras que los niveles de actividad arilesterasa fueron significativamente diferentes entre los grupos estudiados (90 vs. 70 Ul/mL, p= 0.001), sin embargo, al ajustarla por regresión lineal múltiple, dejo de ser significativa. Conclusión: Los polimorfismos Q192R y L55M, y la actividad paraoxonasa de la PON1 no son factores de riesgo para el infarto cerebral aterotrombótico en este estudio.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Encefálica/genética , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Arildialquilfosfatase/genética , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Estudos de Casos e Controles , Modelos Lineares , Isquemia Encefálica/patologia , Projetos Piloto , Reação em Cadeia da Polimerase , Fatores de Risco , Acidente Vascular Cerebral/patologia , Alelos , Frequência do Gene , Genótipo , MéxicoRESUMO
INTRODUCTION: The NR4A2 transcription factor is important in the development, survival and phenotype of dopaminergic neurons and it is postulated as a possible biomarker for Parkinson's disease (PD). Therefore, our aim was to analyze in a sample of a Mexican population with idiopathic PD, mutations (in two hotspot mutation regions) and two polymorphisms (rs34884856 in promotor and rs35479735 intronic regions) of the NR4A2 gene. We also evaluate the levels of NR4A2 gene expression in peripheral blood for a Mexican population, and identify whether they are associated with NR4A2 gene polymorphisms. METHODS: We conducted a case-control study, which included 227 idiopathic PD cases and 454 unrelated controls. Genetic variants of the NR4A2 gene were genotyped by high-resolution melting (HRM) and validated by an automated sequencing method. The gene expression was performed in peripheral blood using a real-time polymerase chain reaction. RESULTS: The rs35479735 polymorphism was associated with a higher risk of developing PD. In addition, NR4A2 gene expression was significantly decreased in patients with PD. Linkage disequilibrium analysis showed a haplotype H4 (3C-3G) that showed lower levels of expression, and contained the risk alleles for both polymorphisms. CONCLUSIONS: In summary, this is the first study in a Mexican population that considers the analysis of NR4A2 in patients with PD. An association was identified between genotype and mRNA expression levels of NR4A2 in patients with PD. These results suggest that polymorphisms and expression of the NR4A2 gene could play an important role in the risk of developing PD in Mexican populations.
Assuntos
Estudos de Associação Genética/métodos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Polimorfismo Genético/genética , Vigilância da População , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Expressão Gênica , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Doença de Parkinson/diagnóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genéticaRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dementia is a frequent complication of idiopathic Parkinsonism or PD, usually occurring later in the protracted course of the illness. Some risk factors to develop dementia in PD are aging, severe Parkinson´s symptoms, rigid-akinetic form, hallucinations, and mild cognitive impairment documented at the first examinations. It is not yet clear if some genetic factors are either risk or protector for progression to dementia. In a review of the literature, we found that mutations in the alpha-synuclein gene are the most responsible for developing dementia, either from PARK1 or 4 mutations. GBA (glucocerebrosidase) is another accountable factor. However, the vast majority of patients suffer from non-Mendelian or complex forms of PD, which are likely caused by the combined effects of genetic and environmental factors. There is not until now a clear relation between some polymorphisms in candidate genes and cognitive deterioration, as many studies have not clearly identified this phenotype.
Assuntos
Demência/etiologia , Predisposição Genética para Doença , Doença de Parkinson/complicações , Demência/genética , Glucosilceramidase/genética , Humanos , Doença por Corpos de Lewy/genética , Mutação , Doença de Parkinson/genética , Fenótipo , Fatores de Risco , alfa-Sinucleína/deficiência , alfa-Sinucleína/genéticaRESUMO
O-hexyl 2,5-dichlorophenyl phosphoramidate (HDCP) is a racemic organophosphate compound (OP) that induces delayed neuropathy in vivo. The O-hexyl 2,5-dichlorophenyl phosphoramidate R (R-HDCP) isomer inhibits and ages neuropathic target esterase (NTE) in hen brain. Moreover, human serum paraoxonase-1 (PON1) is a Ca(2+)-dependent enzyme capable of hydrolyzing OPs. The enzymatic activity of PON1 against OPs depends on the genetic polymorphisms present at position 192 (glutamine or arginine). The catalytic efficiency of PON1 is an important factor that determines neurotoxic susceptibility to some OPs. In the present study, we characterized the stereospecific hydrolysis of HDCP by alloforms PON1 Q192R human serum by chiral chromatography. Forty-seven human samples were characterized for the PON1 192 polymorphism. The hydrolysis data demonstrate that the three alloforms of PON1 show an exclusive and significant stereospecific Ca(2+)-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate S isomer (S-HDCP) at 19-127 µM at the concentrations that remain in all the samples. This stereoselective Ca(2+)-dependent hydrolysis of S-HDCP is inhibited by EDTA and is independent of the PON1 Q192R alloform. The present research reinforces the hypothesis that R-HDCP (an isomer that inhibits and causes NTE aging) is the enantiomer that induces delayed neuropathy by this chiral phosphoramidate due to the low hydrolysis level of the R-HDCP observed in this study.
Assuntos
Arildialquilfosfatase/genética , Síndromes Neurotóxicas/etiologia , Compostos Organofosforados/toxicidade , Polineuropatias/induzido quimicamente , Adulto , Cálcio/metabolismo , Feminino , Humanos , Hidrólise , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/química , Polimorfismo Genético , EstereoisomerismoRESUMO
AIM: In previous CYP2D6 genotyping studies in Mexican-Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. MATERIALS & METHODS: In the present study we evaluated the hypothesis of low frequency of PMs in Mexican-Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. RESULTS: The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. CONCLUSION: The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican-Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations.
Assuntos
Citocromo P-450 CYP2D6/genética , Variações do Número de Cópias de DNA/genética , Indígenas Norte-Americanos/genética , Adulto , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , MéxicoRESUMO
BACKGROUND: The expression of apolipoprotein E (apoE) polymorphisms has been proposed as a risk factor for early development of psychotic symptoms in patients with Parkinson's disease. The association between apoE polymorphisms and motor complications is controversial. The aim was to determine the association between apoE polymorphisms and its allele frequency with the development of complications secondary to dopaminergic replacement therapy. METHODS: We evaluated 231 patients with the diagnosis of Parkinson's disease. The presence of motor complications secondary to treatment was determined by a neurologist, and the genotypification of apoE polymorphisms was performed. Descriptive statistics and chi-squared test were used. RESULTS: Genotype ?3/?3 was expressed in 80.5 % of the sample; there was no association between genotype or allele frequency of apoE polymorphisms and the development of psychosis or dyskinesia. Patients who expressed the ?2 allele showed a tendency to develop motor fluctuations, but without reaching statistical significance (p = 0.08). CONCLUSIONS: ApoE polymorphisms are not associated with the development of complications from dopaminergic replacement therapy.
INTRODUCCIÓN: se ha propuesto que la expresión de los polimorfismos de la apolipoproteína E (apoE) es un factor predisponente para el desarrollo temprano de psicosis en los pacientes con enfermedad de Parkinson. La relación entre el genotipo de la apoE y el desarrollo de complicaciones motoras es controvertida. El objetivo de esta investigación fue determinar la relación entre los polimorfismos de la apoE y su frecuencia alélica y el desarrollo de complicaciones secundarias al reemplazo dopaminérgico. MÉTODOS: se evaluaron 231 pacientes con diagnóstico de enfermedad de Parkinson. La presencia de complicaciones fue determinada por un neurólogo y se realizó la genotipificación de los polimorfismos de la apoE. Se utilizó la chi cuadrada para determinar la relación entre la presencia o ausencia de las complicaciones estudiadas y el genotipo de la apoE. RESULTADOS: se identificó el genotipe ?3/?3 en 80.5 % de la muestra. No existió relación entre el genotipo o la frecuencia alélica de los polimorfismos de la apoE y el desarrollo de psicosis o discinesias. Los pacientes que expresaron el alelo ?2 mostraron una tendencia al desarrollo de fluctuaciones, pero sin significación estadística (p = 0.08). CONCLUSIONES: los polimorfismos de la apoE no se relacionaron con el desarrollo de complicaciones derivadas del reemplazo dopaminérgico. El tratamiento de la enfermedad de Parkinson se basa principalmente en la administración de precursores de la dopamina (como la levodopa) o de agonistas dopaminérgicos.
Assuntos
Antiparkinsonianos/efeitos adversos , Apolipoproteínas E/genética , Dopaminérgicos/efeitos adversos , Discinesias/etiologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Transtornos Psicóticos/etiologia , Adulto , Antiparkinsonianos/uso terapêutico , Estudos Transversais , Dopaminérgicos/uso terapêutico , Feminino , Frequência do Gene , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Polimorfismo Genético , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Vasovagal syncope is a common clinical condition, consequential to reduced cerebral blood flow resulting from a failure in cardiovascular homeostasis during orthostasis. Blood pressure regulation is the basis for syncope development. In this regulation, the α1a-adrenergic receptor plays a major role. Some studies have found a positive correlation between the Arg347Cys polymorphism of the α1a-adrenergic receptor to hypertension and heart autonomic control. The goal of this study is to evaluate the possible association between the Arg347Cys α1a-adrenergic receptor polymorphism and vasovagal syncope in a Mexican population. METHODS/MAJOR FINDINGS: A sample of 89 vasovagal syncope patients and 40 healthy controls were studied. Arg347Cys α1a-adrenergic receptor polymorphism was determined by the PCR-RFLP method. We found an increased frequency of genotype ArgArg in vasovagal syncope patients. In a logistic regression model significant associations were found in two genetic models, in codominant model (OR=13.21: CI 95% 3.69-54.99, p<0.001) and in additive model (OR=12.68: CI 95% 3.5-53.07, p<0.001) for ArgArg genotype with CysCys as reference. CONCLUSIONS: Our data suggests an important participation of Arg347Cys polymorphism as susceptibility factor in patients with vasovagal syncope. ArgArg genotype could be a marker for vasovagal syncope susceptibility in the Mexican population.