RESUMEN
There is evidence that increased concentrations of circulating homocysteine are associated with Alzheimer's disease (AD). Phosphatidylethanolamine N-methyltransferase (PEMT) is an important catalyst involved in the production of homocysteine. We investigated the association of a functional single nucleotide polymorphism (rs7946) in PEMT with sporadic AD risk in a Han Chinese population that included 386 AD patients and 366 controls. PEMT G523A was genotyped by either sequencing or PCR-restriction fragment length polymorphism analysis. The plasma homocysteine concentrations of 210 subjects were determined by high-performance liquid chromatography. Significant higher frequency of the A allele was detected in AD cases than in controls (A vs. G, p = 0.007, OR = 1.482, 95% CI 1.114-1.972). After adjusting for gender, age/age at onset, and APOE ε4 status, logistic analysis showed rs7946 was associated with AD in a dominant model (AA + GA vs. GG, p = 0.007, OR = 1.596, 95% CI 1.138-2.240). When stratified by APOE ε4 status or gender, the significant difference was only observed in the APOE ε4 non-carriers and in the female subjects, respectively. We did not find a relationship of this polymorphism with plasma homocysteine levels. These results suggested that PEMT G523A is associated with AD and that the A allele is an APOE ε4-independent risk factor for AD among Han Chinese women.
Asunto(s)
Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/genética , Fosfatidiletanolamina N-Metiltransferasa/genética , Anciano , Enfermedad de Alzheimer/enzimología , Sustitución de Aminoácidos/genética , Pueblo Asiatico/genética , China/epidemiología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de RiesgoRESUMEN
Expression profiling of microRNAs (miRNAs) in most diseases might be popular and provide the possibility for diagnostic implication, but few studies have accurately quantified the expression level of dysregulated miRNAs in acute myeloid leukemia (AML). In this study, we analyzed the peripheral blood mononuclear cells (PBMCs) from 10 AML patients (subtypes M1 to M5) and six normal controls by miRNA microarray and identified several differentially expressed miRNAs. Among them miR-29a and miR-142-3p were selectively encountered in Northern blot analysis and their significantly decreased expression in AML was further confirmed. Quantitative real-time PCR in 52 primarily diagnosed AML patients and 100 normal controls not only verified the expression properties of these 2 miRNAs, but also established that the expression level of miR-142-3p and miR-29a in PBMCs could be used as novel diagnostic markers. A better diagnostic outcome was achieved by combining miR-29a and miR-142-3p with about 90% sensitivity, 100% specificity, and an area under the ROC curve (AUC) of 0.97. Our results provide insights into the involvement of miRNAs in leukemogenesis, and offer candidates for AML diagnosis and therapeutic strategy.
Asunto(s)
Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica/genética , Leucemia Mieloide Aguda/genética , MicroARNs/metabolismo , Área Bajo la Curva , Northern Blotting , Perfilación de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucocitos Mononucleares/metabolismo , Análisis por Micromatrices , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
Leukocyte telomere length is widely considered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also positively associated with several measures of healthy aging, but this relationship was dependent on age. We screened two genes known to be involved in telomere maintenance for association with the age-related decline in telomere length observed in our population to identify candidate longevity-associated genes. A single-nucleotide polymorphism located in the SIRT1 gene and another in the 3' flanking region of XRCC6 had significant effects on telomere length. At each bi-allelic locus, the minor variant was associated with longer telomeres, though the mode of inheritance fitting best differed between the two genes. No statistical interaction was detected for telomere length between the SIRT1 and XRCC6 variants or between these polymorphisms and age. The SIRT1 locus was significantly associated with longevity (P < 0.003). The frequency of the minor allele was higher in long-lived cases than in young controls, which coincides with the protective role of the minor variant for telomere length. In contrast, the XRCC6 variant was not associated with longevity. Furthermore, it did not affect the association of SIRT1 with exceptional survival. The association of the same variant of SIRT1 with longevity was near significant (P < 0.07) in a second population. These results suggest a potential role of SIRT1 in linking telomere length and longevity. Given the differences between this gene and XRCC6, they point to the distinct impact that alternate pathways of telomere maintenance may have on aging and exceptional survival.
Asunto(s)
Antígenos Nucleares/genética , Proteínas de Unión al ADN/genética , Longevidad/genética , Polimorfismo de Nucleótido Simple , Sirtuina 1/genética , Acortamiento del Telómero , Telómero/metabolismo , Región de Flanqueo 3' , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antígenos Nucleares/metabolismo , Estudios de Casos y Controles , Proteínas de Unión al ADN/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Georgia , Humanos , Autoantígeno Ku , Escala de Lod , Louisiana , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Fenotipo , Modelos de Riesgos Proporcionales , Sirtuina 1/metabolismo , Análisis de Supervivencia , Adulto JovenRESUMEN
Calcium homeostasis is critical to amyloid beta precursor protein (APP) processing. Na(+)/Ca(2+) exchanger (NCX) proteins play an important role in maintaining intracellular Na(+) and Ca(2+) homeostasis in the brain under physiological and pathological conditions. We sequenced a hyper-variable region in intron 2 of the Na(+)/Ca(2+) exchanger 1 gene (NCX1), and investigated whether insertion/deletion variations in this region are associated with the occurrence for Alzheimer's disease (AD). Examining 413 AD patients and 361 healthy controls, we identified 3 insertion/deletion polymorphisms. No significant differences of the allele and genotype frequencies were observed between the AD cases and the controls for any of the three polymorphisms. However, among the AD patients whose age at onset (AAO) was 65 years or older (n = 299), carriers of a 14 bp insertion showed a lower average AAO (ins/ins and ins/del vs. del/del, 72.49 ± 5.17 vs. 74.28 ± 5.79, p = 0.016). It suggested that this 14 bp insertion/deletion polymorphism might modulate AAO in late-onset AD patients.
Asunto(s)
Enfermedad de Alzheimer/genética , Mutación INDEL , Polimorfismo Genético , Intercambiador de Sodio-Calcio/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Intrones , Masculino , Persona de Mediana EdadRESUMEN
The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.
Asunto(s)
Envejecimiento/genética , Apolipoproteínas E/genética , Longevidad/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Variación Genética/genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Esfingosina N-AciltransferasaRESUMEN
Several lines of evidence indicate that fibroblast growth factor 1 (FGF1) confers neuroprotection against excitotocity and contributes to the selective vulnerability of neurons in entorhinal cortex in Alzheimer's disease (AD). Especially, FGF1 is related to Apolipoprotein E (ApoE) expression in reactive astrocytes. Therefore, FGF1 is a promising candidate gene for AD. Two studies reported the association of a polymorphism that is located 1385bp upstream from the initial code of FGF1 gene (FGF1 -1385 C>T) polymorphism with AD. To determine whether this polymorphism could affect AD development, we investigated the association between this polymorphism and AD risk in 372 sporadic AD patients and 349 controls in a Chinese Han population. No significant difference of allele and genotype distributions between the AD cases and the controls was observed in the total samples (for the alleles, chi(2)=0.126; p=0.722; for the genotypes, chi(2)=0.089; p=0.765), neither when the samples were stratified by ApoE epsilon4-carrying status, age/age at onset and gender. Our data suggested no association between the FGF1 -1385 C>T polymorphism and AD risk in Chinese Han population.
Asunto(s)
Enfermedad de Alzheimer/genética , Pueblo Asiatico/genética , Factor 1 de Crecimiento de Fibroblastos/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo Genético/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4/genética , Astrocitos/metabolismo , Astrocitos/patología , Secuencia de Bases/genética , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/etnología , Pruebas Genéticas , Genotipo , Gliosis/genética , Gliosis/patología , Gliosis/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Mutación Puntual/genética , Distribución por SexoRESUMEN
Folate deficiency and elevated plasma homocysteine play important roles in pathogenesis of Alzheimer's disease (AD). The aim of this study was to test the association of folate metabolism-related genes, cystathionine beta-synthase gene (CbetaS) and 5, 10-methylenetetrahydrofolate dehydrogenase gene (MTHFD1), with sporadic AD. The CbetaS 844ins68 polymorphism was determined by PCR and the MTHFD1 G1958A single nucleotide polymorphism (rs2236225) by PCR-RFLP. No significant difference of allele and genotype contributions of the CbetaS polymorphism between AD cases and controls was detected, before and after stratification by APOE epsilon4-carrying status, age/age at onset and genders. No significant difference of allele and genotype contributions of the MTHFD1 polymorphism between AD cases and controls was detected in total samples. When stratified by age/at onset age, we found that A allele and AA genotype frequencies in cases were higher than in controls and the differences were close to significant [A vs. G, P = 0.032, Odds ratio (OR) 1.642, 95% CI 1.040-2.591; AA + GA vs. GG, P = 0.068, OR 1.665, 95% CI 0.961-2.885; AA vs. GG, P = 0.059, OR 3.458, 95% CI 0.894-13.369] in <65 years groups, which suggested that the MTHFD1 G1958A A allele might be a weak risk factor for early onset AD although it needs further confirmation.
Asunto(s)
Enfermedad de Alzheimer/genética , Pueblo Asiatico/genética , Cistationina betasintasa/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Polimorfismo Genético , Anciano , Anciano de 80 o más Años , Alelos , Apolipoproteína E4/genética , Estudios de Casos y Controles , China , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Polimorfismo de Nucleótido SimpleRESUMEN
We examined polymorphisms in reduced folate carrier gene (RFC1) and methylenetetrahydrofolate reductase gene (MTHFR) for association with sporadic AD (SAD) in Chinese population. Significant associations of RFC1 A80G G allele and GG genotype with SAD (p=0.008, OR=1.312, 95%CI=1.072-1.605, and p=0.042, OR=1.383, 95%CI=1.012-1.890) were found. Further stratification of total samples by APOE epsilon4 carrier status, age/age at onset and gender revealed that RFC1 A80G G allele was an APOE epsilon4-independent risk factor for late-onset AD, and it might increase the risk of AD in females. No significant associations of MTHFR C677T allele and genotype with AD were observed in total samples, but significant associations of T allele and TT genotype with AD (p=0.031, OR=1.586, 95%CI=1.042-2.414, and p=0.028, OR=2.250, 95%CI=1.074-4.712) were identified in APOE epsilon4 carrier subgroup, suggesting that MTHFR 677 T allele and APOE epsilon4 allele may synergistically act to increase AD risk. No significant effect of RFC1 G80A and MTHFR C677T polymorphisms on plasma folate and homocysteine levels was detected.
Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Proteína Portadora de Folato Reducido/genética , Anciano , Anciano de 80 o más Años , Envejecimiento , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/epidemiología , China/epidemiología , Femenino , Ácido Fólico/sangre , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Homocisteína/sangre , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores SexualesRESUMEN
Homocysteine has been identified to be associated with Alzheimer disease (AD) and methionine synthase (MS) is one of the enzymes involved in homocysteine metabolism. Confused data were reported on the association between the MS 2756 A>G polymorphism and AD. To determine if this polymorphism could affect the occurrence of AD, we investigated the association between the MS 2756 A>G polymorphism and AD risk in 353 sporadic AD patients and 346 controls in a Chinese Han population. No significant differences of allele and genotype distributions between the AD cases and the controls were observed in the total samples, neither when the samples were stratified by age/age at onset and gender. When the samples were stratified by APOE epsilon4 status, a trend of A allele and AA genotype over-representation in the AD patients in comparison with the controls was observed, but it was not statistically significant (for the alleles, A versus G OR=1.549, 95% CI 0.920-2.609, p=0.098; for the genotypes, AA versus AG+GG OR=1.485, 95% CI 0.861-2.560, p=0.153). Similar trend was observed in the APOE epsilon4 non-carrier samples of the >or=65 year subgroups and it was not statistically significant too (for the alleles, A versus G OR=1.682, 95% CI 0.901-3.140, p=0.099, for the genotypes, AA versus AG+GG OR=1.690, 95% CI 0.884-3.232, p=0.110). Our data did not reveal significant association between the MS 2756 A>G polymorphism and AD development. However, a weak effect of the A allele on developing AD could not be completely excluded.
Asunto(s)
5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Apolipoproteínas E/genética , China/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Escalas de Valoración PsiquiátricaRESUMEN
Several lines of evidence support a role of oxidative stress in the pathology of Alzheimer's disease (AD). NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes the two-electron reduction of quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. We examined association between the NQO1 C609T gene polymorphism and sporadic AD in a Chinese population comprising 311 AD patients and 330 controls. Our results showed a higher T-allele frequency in the AD cases compared with the controls. The difference was close to but did not reach statistically significant level [p = 0.059; odds ratio (OR) T versus C = 1.236; 95% confidence interval (95% CI), 0.992-1.540]. A significantly low C/C genotype frequency in the AD cases compared with the controls was detected (p = 0.025; OR C/C versus C/T + T/T = 0.674; 95% CI, 1.049-2.098) and APOE epsilon4 status analysis revealed significant difference in the APOE epsilon4 non-carriers (p = 0.036; OR = 0.633; 95% CI, 1.027-2.427). In the > or =65 years samples, significantly low C/C frequency in the AD cases in comparison with the controls was observed in the APOE epsilon4 non-carriers (p = 0.045; OR = 0.595; 95% CI, 1.010-2.794). These results indicated that the C/C genotype had a possible protective effect against AD development, and the T allele might be a weak risk factor for late onset AD.