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OBJECTIVES: The aim of this study was the analysis of WNT10A variants in seven families of probands with various forms of tooth agenesis and self-reported family history of cancer. MATERIALS AND METHODS: We enrolled 60 young subjects (aged 13 to 17) from the Czech Republic with various forms of tooth agenesis. Dental phenotypes were assessed using Planmeca ProMax 3D (Planmeca Oy, Finland) with Planmeca Romexis software (version 2.9.2) together with oral examinations. After screening PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes on the Illumina MiSeq platform (Illumina, USA), we further analyzed the evolutionarily highly conserved WNT10A gene by capillary sequencing in the seven families. RESULTS: All the detected variants were heterozygous or compound heterozygous with various levels of phenotypic expression. The most severe phenotype (oligodontia) was found in a proband who was compound heterozygous for the previously identified WNT10A variant p.Phe228Ile and a newly discovered c.748G > A variant (p.Gly250Arg) of WNT10A. The newly identified variant causes substitution of hydrophobic glycine for hydrophilic arginine. CONCLUSIONS: We suggest that the amino acid changes in otherwise highly conserved sequences significantly affect the dental phenotype. No relationship between the presence of WNT10A variants and a risk of cancer has been found. CLINICAL RELEVANCE: Screening of PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes in hope to elucidate the pattern of inheritance in families.
Assuntos
Anodontia , Neoplasias , Humanos , Anodontia/genética , República Tcheca , Mutação , Fenótipo , Autorrelato , Proteínas Wnt/genética , AdolescenteRESUMO
The risk of Alzheimer's disease (AD) has a strong genetic component, also in the case of late-onset AD (LOAD). Attempts to sequence whole genome in large populations of subjects have identified only a few mutations common to most of the patients with AD. Targeting smaller well-characterized groups of subjects where specific genetic variations in selected genes could be related to precisely defined psychological traits typical of dementia is needed to better understand the heritability of AD. More than one thousand participants, categorized according to cognitive deficits, were assessed using 14 psychometric tests evaluating performance in five cognitive domains (attention/working memory, memory, language, executive functions, visuospatial functions). CD36 was selected as a gene previously shown to be implicated in the etiology of AD. A total of 174 polymorphisms were tested for associations with cognition-related traits and other AD-relevant data using the next generation sequencing. Several associations between single nucleotide polymorphisms (SNP's) and the cognitive deficits have been found (rs12667404 with language performance, rs3211827 and rs41272372 with executive functions, rs137984792 with visuospatial performance). The most prominent association was found between a group of genotypes in six genetically linked and the age at which the AD patients presented with, or developed, a full-blown dementia. The identified alleles appear to be associated with a delay in the onset of LOAD. In silico studies suggested that the SNP's alter the expression of CD36 thus potentially affecting CD36-related neuroinflammation and other molecular and cellular mechanisms known to be involved in the neuronal loss leading to AD. The main outcome of the study is an identification of a set of six new mutations apparently conferring a distinct protection against AD and delaying the onset by about 8 years. Additional mutations in CD36 associated with certain traits characteristic of the cognitive decline in AD have also been found.
Assuntos
Doença de Alzheimer , Antígenos CD36 , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Antígenos CD36/genética , Função Executiva/fisiologia , Humanos , Mutação , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Insulin-degrading enzyme (IDE) is a widely distributed Zn2+-binding metalloprotease that cleaves multiple short and medium-sized peptides prone to form ß-structures. These include insulin and amyloid-ß peptides. Accumulation and fibrillation of amyloid-ß peptides leading to the formation of amyloid plaques is a characteristic sign of Alzheimer's disease (AD) pathology. OBJECTIVE: The study investigated the rs2421943 single nucleotide polymorphism (SNP) of the IDE gene as a risk factor for MCI (mild cognitive impairment) and AD. METHODS: Two independent groups of 1670 patients and controls were included. The AD group consisted of 595 patients and 400 controls; the MCI group involved 135 patients and 540 matched controls. PCR and restriction fragment length analysis were used to analyze the rs2421943 polymorphism. Using the miRBase and RNA22 prediction tools in silico indicated that the rs2421943 polymorphism is a potential target for a specific miRNA (hsa-miR-7110-5p). RESULTS: AG and GG genotypes of rs2421943 significantly increased the risk of AD, and the AG genotype increased the risk of MCI. It seems the G allele both increases the risk of AD and accelerates the transition through the MCI phase. In silico study revealed that rs2421943 is inside the sequence binding miRNA hsa-miR-7110-5p. The polymorphism could affect the rate of IDE pre-RNA (heterogeneous nuclear RNA, hnRNA) processing, resulting in slower translation, lower levels of IDE, deficient removal of amyloid-ß fragments, and greater risk of and/or accelerated progression of AD. CONCLUSION: GG and AG genotypes of the single nucleotide polymorphism rs2421943 of insulindegrading enzyme gene increase the risk of AD and MCI.
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Doença de Alzheimer , Insulisina , MicroRNAs , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Humanos , Insulisina/genética , Insulisina/metabolismo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected energy metabolism, oxidation and the production of actaldehyde and acetate; this could have specific consequences not only for the brain energy production/utilization but could influence the cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain metabolism of ethanol occurs to any significant degree; the reduction in glucose metabolism following alcohol consumption is due to ethanol effects on receptors, such as α4ß3δ GABA(A) receptors. Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic brains identified a large number of proteins, the expression of which was altered by chronic alcohol, with those associated with brain energy metabolism among the most numerous. Neurochemical studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant proteins in the nervous tissue and is intimately associated with the function of the excitatory (glutamatergic) synapses, this may be among the most important effects of chronic alcohol on brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the severity of alcoholism in human males. We conclude that the reviewed studies present a unique set of data which could help to predict the risk of developing alcohol dependence (genetics), to improve the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics) and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism and alcohol addiction.
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Alcoolismo/genética , Alcoolismo/metabolismo , Etanol/metabolismo , Acetilação , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Encéfalo , Epigênese Genética , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Histonas/metabolismo , Humanos , Metabolômica , Proteômica , Receptores de GABA/metabolismo , Transdução de SinaisRESUMO
Several single-nucleotide polymorphisms (SNPs) and rare variants of non-receptor tyrosine kinase 1 gene (TNK1) have been associated with Alzheimer's disease (AD). To date, none of the associations have proven to be of practical importance in predicting the risk of AD either because the evidence is not conclusive, or the risk alleles occur at very low frequency. In the present study, we are evaluating the associations between rs11867353 polymorphism of TNK1 gene and both AD and mild cognitive impairment (MCI) in a group of 1656 persons. While the association with AD was found to be highly statistically significant (p < 0.0001 for the risk genotype CC), no statistically significant association with MCI could be established. Possible explanation of the apparent discrepancy could be rapid progression of MCI to AD in persons with the CC genotype. Additional findings of the study are statistically significant associations of rs11867353 polymorphism with body mass index, body weight, and body height. The patients with AD and CC genotype had significantly lower values of body mass index and body weight compared with patients with other genotypes. The main outcome of the study is the finding of a previously never described association between the rs11867353 polymorphism of the TNK1 gene and AD. The rs11867353 polymorphism has a potential to become a significant genetic marker when predicting the risk of AD.
Assuntos
Doença de Alzheimer/genética , Proteínas Fetais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Proteínas Tirosina Quinases/genética , Idoso , Estatura , Índice de Massa Corporal , Peso Corporal , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Humanos , MasculinoRESUMO
Clusterin (CLU; also known as apolipoprotein J, ApoJ) is a protein of inconstant structure known to be involved in diverse processes inside and outside of brain cells. CLU can act as a protein chaperon or protein solubilizer, lipid transporter as well as redox sensor and be anti- or proapoptotic, depending on context. Primary structure of CLU is encoded by CLU gene which contains single nucleotide polymorphisms (SNP's) associated with the risk of late-onset Alzheimer's disease (LOAD). Studying a sample of Czech population and using the case-control association approach we identified C allele of the SNP rs11136000 as conferring a reduced risk of LOAD, more so in females than in males. Additionally, data from two smaller subsets of the population sample suggested a possible association of rs11136000 with diabetes mellitus. In a parallel study, we found no association between rs11136000 and mild cognitive impairment (MCI). Our findings on rs11136000 and LOAD contradict those of some previous studies done elsewhere. We discuss the multiple roles of CLU in a broad range of molecular mechanisms that may contribute to the variability of genetic studies of CLU in various ethnic groups. The above discordance notwithstanding, our conclusions support the association of rs1113600 with the risk of LOAD.
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Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Clusterina/genética , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , República Tcheca , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de RiscoAssuntos
Arteríolas/patologia , Vasos Retinianos/patologia , Esquizofrenia/patologia , Vênulas/patologia , Adolescente , Adulto , Idoso , Arteríolas/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vasos Retinianos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Vênulas/diagnóstico por imagem , Adulto JovemRESUMO
OBJECTIVES: We used mice as an animal model to investigate the entry of ZnO nanoparticles from the ambient air into the lungs and other organs, subsequent changes in Zn levels and the impact on the transcription of Zn homeostasis-related genes in the lungs. METHODS: The mice were exposed to two concentrations of ZnO nanoparticles; lower (6.46â¯×â¯104 particles/cm3) and higher (1.93â¯×â¯106 particles/cm3), allowed to breathe the nanoparticles in the air for 12 weeks and subjected to necropsy. Characterization of the ZnO nanoparticles was done using transmission electron microscopy (TEM). Energy-dispersive X-ray (EDX) spectroscopy was used to quantify ZnO nanoparticles in the lungs, brain, liver and kidney. The total zinc content in the lungs, brain, liver, kidney, red blood cells and plasma was estimated by inductively coupled plasma mass spectroscopy (ICP-MS). Transcription rate of the genes was evaluated by RealTime PCR. RESULTS: The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (pâ¯<â¯0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (pâ¯<â¯0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes. CONCLUSION: Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.
RESUMO
Excitatory amino acid transporter 5 (EAAT5) is a protein that is known to be alternately spliced and to be abundantly expressed in the retina by populations of neurons including photoreceptors and bipolar cells. EAAT5 acts as a slow glutamate transporter and also as glutamate-gated chloride channel, the chloride conductance being large enough for EAAT5 to serve functionally as an "inhibitory" glutamate receptor. However, there has been a long-standing view that the classically spliced form of EAAT5 is not abundant or widespread in the brain and so it has not been extensively investigated in the literature. We recently identified a human-specific splicing form of EAAT5 that was not expressed by rodents but was shown to be a functional glutamate transporter. We have examined the expression of this form of EAAT5, hEAAT5v at the mRNA, and protein level in human brain, and show that populations of human cortical pyramidal neurons and cerebellar Purkinje cells show significant expression of hEAAT5v. Accordingly, we infer that EAAT5 may well be a player in modulating neuronal function in the human brain and propose that its localization in both glutamatergic and GABAergic neurons could be compatible with a role in influencing intracellular chloride and thereby neuronal parameters such as membrane potential rather than acting as a presynaptic glutamate transporter.
Assuntos
Encéfalo/citologia , Encéfalo/metabolismo , Transportador 5 de Aminoácido Excitatório/biossíntese , Transportador 5 de Aminoácido Excitatório/genética , Neurônios/metabolismo , Animais , Expressão Gênica , Humanos , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , RatosRESUMO
PURPOSE: We investigated associations between neovascular age-related macular degeneration (AMD) and rs10490924 polymorphism of ARMS2 gene (age-related maculopathy susceptibility 2), rs1061170 polymorphism of gene for complement factor H (CFH), rs2230199 polymorphism of gene for complement component C3 and rs11200638 polymorphism of gene for serine protease high-temperature requirement A1 (HTRA1) in the Czech population. METHODS: We analysed samples of DNA from 307 patients diagnosed with neovascular form of late AMD (average age: 73.7 ± 7.7 years) and 191 control subjects, recruited from patients awaiting cataract surgery (average age, 73.6 ± 8.7 years). RESULTS: HTRA1, CFH and ARMS2 genes polymorphisms were found to be related to neovascular AMD in the Czech population. All analysed polymorphisms were statistically significantly associated with neovascular AMD, with stronger associations in females than in males. In whole group, CC genotype of CFH gene polymorphism, TT genotype of ARMS2 gene polymorphism and AA genotype of HTRA1 gene polymorphism showed the greatest risk for neovascular AMD with odds ratios equal to 8.43, 10.07, 9.83, respectively (p < 0.0001). Only CG polymorphism of C3 gene showed statistically significant risk for neovascular AMD. In addition, we observed an association between waist circumference and neovascular AMD in both sexes, which further suggests the significance of excessive abdominal fat as a risk factor of AMD. We found a statistically significant association between polymorphisms in HTRA1, CFH and ARMS2 genes and neovascular AMS in the Czech population. The association was stronger in females than in males. CONCLUSION: We demonstrated a relationship between neovascular AMD and genes for HTRA1, CFH, ARMS2 and C3 in Czech population. To our knowledge, the relationship between these polymorphisms and neovascular AMD in Czech population has never been investigated before.
Assuntos
Complemento C3/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Degeneração Macular/genética , Proteínas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Fator H do Complemento/genética , República Tcheca , Feminino , Humanos , Masculino , Obesidade Abdominal/complicações , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores SexuaisRESUMO
We have analysed post-mortem samples of prefrontal cortex from control and alcoholic human brains by the technique of Western blotting to estimate and compare the expressions of glutamate transporter GLAST (Excitatory Amino Acid Transporter One; EAAT1). Furthermore, using the non-alcoholic prefrontal cortex and custom-made GLAST (EAAT1) antibody we determined GLAST (EAAT1) "interactome" i.e. the set of proteins selectively bound by GLAST (EAAT1). We found that GLAST (EAAT1) was significantly more abundant (about 1.6-fold) in the cortical tissue from alcoholic brains compared to that from non-alcoholic controls. The greatest increase in the level of GLAST (EAAT1) was found in plasma membrane fraction (2.2-fold). Additionally, using the prefrontal cortical tissue from control brains, we identified 38 proteins specifically interacting with GLAST (EAAT1). These can be classified as contributing to the cell structure (6 proteins; 16%), energy and general metabolism (18 proteins; 47%), neurotransmitter metabolism (three proteins; 8%), signalling (6 proteins: 16%), neurotransmitter storage/release at synapses (three proteins; 8%) and calcium buffering (two proteins; 5%). We discuss possible consequences of the increased expression of GLAST (EAAT1) in alcoholic brain tissue and whether or how this could disturb the function of the proteins potentially interacting with GLAST (EAAT1) in vivo. The data represent an extension of our previous proteomic and metabolomic studies of human alcoholism revealing another aspect of the complexity of changes imposed on brain by chronic long-term consumption of ethanol.
Assuntos
Alcoolismo/metabolismo , Transportador 1 de Aminoácido Excitatório/biossíntese , Metabolômica/métodos , Córtex Pré-Frontal/metabolismo , Proteômica/métodos , Adulto , Idoso , Alcoólicos , Alcoolismo/genética , Alcoolismo/patologia , Transportador 1 de Aminoácido Excitatório/genética , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/patologiaRESUMO
Tooth agenesis is one of the most common craniofacial disorders in humans. More than 350 genes have been associated with teeth development. In this study, we enrolled 60 child patients (age 13 to 17) with various types of tooth agenesis. Whole gene sequences of PAX9, MSX1, AXIN2, EDA, EDAR and WNT10a genes were sequenced by next generation sequencing on the Illumina MiSeq platform. We found previously undescribed heterozygous nonsense mutation g.8177G>T (c.610G>T) in MSX1 gene in one child. Mutation was verified by Sanger sequencing. Sequencing analysis was performed in other family members of the affected child. All family members carrying g.8177G>T mutation suffered from oligodontia (missing more than 6 teeth excluding third molars). Mutation g.8177G>T leads to a stop codon (p.E204X) and premature termination of Msx1 protein translation. Based on previous in vitro experiments on mutation disrupting function of Msx1 homeodomain, we assume that the heterozygous g.8177G>T nonsense mutation affects the amount and function of Msx1 protein and leads to tooth agenesis.
Assuntos
Anodontia/genética , Códon sem Sentido , Fator de Transcrição MSX1/genética , Adolescente , Anodontia/patologia , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Unhas Malformadas , LinhagemRESUMO
Developing brain cells express many proteins but little is known of how their protein composition responds to chronic exposure to alcohol and/or how such changes might relate to alcohol toxicity. We used cultures derived from embryonic rat brain (previously shown to contain mostly neural stem cells; rat NSC, rNSC), exposed them to ethanol (25-100 mM) for up to 96 h and studied how they reacted. Ethanol (50 and 100 mM) reduced cell numbers indicating either compromised cell proliferation, cytotoxicity or both. Increased lipid peroxidation was consistent with the presence of oxidative stress accompanying alcohol-induced cytotoxicity. Proteomics revealed 28 proteins as altered by ethanol (50 mM for 96 h). Some were constituents of cytoskeleton, others were involved in transcription/translation, signal transduction and oxidative stress. Nucleophosmin (NPM1) and dead-end protein homolog 1 (DND1) were further studied by immunological techniques in cultured neurons and astrocytes (derived from brain tissue at embryonic ages E15 and E20, respectively). In the case of DND1 (but not NPM1) ethanol induced similar pattern of changes in both types of cells. Given the critical role of the protein NPM1 in cell proliferation and differentiation, its reduced expression in the ethanol-exposed rNSC could, in part, explain the lower cells numbers. We conclude that chronic ethanol profoundly alters protein composition of rNSC to the extent that their functioning-including proliferation and survival-would be seriously compromised. Translated to humans, such changes could point the way towards mechanisms underlying the fetal alcohol spectrum disorder and/or alcoholism later in life.
Assuntos
Astrócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Etanol/toxicidade , Células-Tronco Neurais/efeitos dos fármacos , Animais , Células Cultivadas , Citoesqueleto/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/efeitos dos fármacos , Nucleofosmina , RatosRESUMO
BACKGROUND: Cholinergic hypothesis of Alzheimer's disease (AD) is based on the findings that a reduced and/or perturbed cholinergic activity in the central nervous system correlates with cognitive decline in patients with Alzheimer's disease. The hypothesis resulted in the development of centrally-acting agents potentiating cholinergic neurotransmission; these drugs, however, only slowed down the cognitive decline and could not prevent it. Consequently, the perturbation of the central cholinergic signalling has been accepted as a part of the Alzheimer's aetiology but not necessarily the primary cause of the disease. In the present study we have focused on the rs3810950 polymorphism of ChAT (choline acetyltransferase) gene that has not been studied in Czech population before. METHODS: We carried out an association study to test for a relationship between the rs3810950 polymorphism and Alzheimer's disease in a group of 1186 persons; 759 patients with Alzheimer's disease and 427 control subjects. Furthermore, we performed molecular modelling of the terminal domain (1st-126th amino acid residue) of one of the ChAT isoforms (M) to visualise in silico whether the rs3810950 polymorphism (A120T) can change any features of the tertiary structure of the protein which would have a potential to alter its function. RESULTS: The AA genotype of CHAT was associated with a 1.25 times higher risk of AD (p < 0.002) thus demonstrating that the rs3810950 polymorphism can have a modest but statistically significant effect on the risk of AD in the Czech population. Furthermore, the molecular modelling indicated that the polymorphism is likely to be associated with significant variations in the tertiary structure of the protein molecule which may impact its enzyme activity. CONCLUSIONS: Our findings are consistent with the results of the meta-analytical studies of the relationship between rs3810950 polymorphism and AD and provide further material evidence for a direct (primary) involvement of cholinergic mechanisms in the etiopathogenesis of AD, particularly as a factor in cognitive decline and perturbed conscious awareness commonly observed in patients with AD.
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Colina O-Acetiltransferase/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Colina O-Acetiltransferase/metabolismo , República Tcheca , Feminino , Genótipo , Humanos , MasculinoRESUMO
BACKGROUND: The wet form of age-related macular degeneration (AMD) is characterized by pathological vascularization of the outer retinal layers. The condition responds to treatment with antibodies against vascular endothelial growth factor (VEGF), but the patients receiving such anti-VEGF therapy sometimes show undesirable acute short-term increases in the intraocular pressure (IOP). The cause of this adverse effect is unknown, and here, we are testing a hypothesis that it is related to CD36 gene polymorphisms. MATERIALS AND METHODS: A group of 134 patients with AMD were given three therapeutic doses of anti-VEGF antibody (ranibizumab) at monthly intervals. Their IOP was measured immediately before and 30 min after each injection. Patients' DNA was analyzed, and the changes in IOP were matched against seven polymorphisms of the CD36 gene. RESULTS: Three polymorphisms were found to be associated with increases in IOP: rs1049673 (p = 0.006), rs3211931 (p = 0.01), and rs1761667 (p = 0.043) at the time of the third injection only. Pronounced elevations (IOP > 25 mmHg) were associated with rs1049673 polymorphism: GC genotype (p < 0.01) and CC genotype (p < 0.05); both increasing the risk 2.6-fold, the presence of C-allele conferring a 1.5-fold greater risk and with rs3211931 polymorphism: AG genotype (p < 0.01) and GG genotype (p < 0.05); increasing the risk 2.6-fold (AG) and 2.7-fold (GG). CONCLUSIONS: CD36 receptor may be involved in mediating the effects of VEGF on IOP. The findings will help to identify the patients at risk of acutely elevated IOP following the anti-VEGF therapy.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antígenos CD36/genética , Pressão Intraocular/genética , Hipertensão Ocular/genética , Polimorfismo de Nucleotídeo Único , Ranibizumab/uso terapêutico , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Feminino , Humanos , Injeções Intravítreas , Masculino , Reação em Cadeia da Polimerase , Tonometria Ocular , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/genéticaRESUMO
AXIN2 gene plays a crucial role in morphogenesis of craniofacial area and is essential for tooth development. AXIN2 gene is one of the most studied genes associated with tooth agenesis, the most common defect of dentition in humans. Polymorphic variants in AXIN2 gene are discussed in relation to the occurrence of the tooth agenesis but also as an indication of the risk of cancer. Mutations in AXIN2 gene were found in patients with colorectal or hepatocellular carcinoma, prostate cancer, ovarium or lung cancer. These findings support the hypothesis that missing teeth may be a significant marker for predisposition for cancer.
Assuntos
Anodontia/genética , Proteína Axina/genética , Neoplasias/genética , Predisposição Genética para Doença , Genótipo , Humanos , Mutação , Polimorfismo Genético , Fatores de RiscoRESUMO
CD36 gene encodes a membrane glycoprotein (type B scavenger receptor) present on the surface of many types of cells and having multiple cellular functions ranging from angiogenesis to gustatory perception of fatty acids. Using a case control genetic association approach we have analyzed selected single nucleotide polymorphisms (SNP's) in a total of 859 patients with Alzheimer's disease (AD) and controls and have identified the allele A in rs3211892 polymorphism of CD36 gene as significantly increasing the risk of AD. Additionally we have investigated, in the same sample of control subjects and patients, SNP's in ApoE gene and confirmed that the previously identified AD-associated SNP's indeed increased the risk and decreased the age of onset of AD as reported by others earlier. Based on the current knowledge of CD36 biochemistry we propose that the AD risk-imparting variants of CD36 alter cholesterol homeostasis, oxidation stress or induce pathological inflammatory cascades. The SNP rs3211892 has previously been associated with heart disease and other conditions but the present study is the first to identify a significant association between variations in CD36 gene and the risk of Alzheimer's disease.
Assuntos
Doença de Alzheimer/genética , Antígenos CD36/genética , Polimorfismo Genético/genética , Idoso , Doença de Alzheimer/metabolismo , Colesterol/metabolismo , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
It has been known that a preconception paternal alcoholism impacts adversely on the offspring but the mechanism of the effect is uncertain. Several findings suggest that there are signalling systems in testis that are analogous to those known to be altered by alcoholism in brain. We propose that chronic alcohol affects these systems in a manner similar to that in brain. Specifically, we hypothesise that excessive alcohol may disturb glutamatergic-like signalling in testis by increasing expression of the glutamate transporter GLAST (EAAT1). We discuss ways how to test the hypothesis as well as potential significance of some of the tests as tools in the diagnostics of chronic alcoholism.
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Consumo de Bebidas Alcoólicas , Encéfalo/patologia , Etanol/química , Transportador 1 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Testículo/metabolismo , Alcoolismo/fisiopatologia , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Transporte Biológico , Anormalidades Congênitas/etiologia , Pai , Feminino , Glutamina/metabolismo , Humanos , Masculino , Camundongos , Modelos Biológicos , Exposição Paterna , Risco , Transdução de SinaisRESUMO
Dementias of old age, in particular Alzheimer's disease (AD), pose a growing threat to the longevity and quality of life of individuals as well as whole societies world-wide. The risk factors are both genetic and environmental (life-style) and there is an overlap with similar factors predisposing to cardiovascular diseases (CVD). Using a case-control genetic approach, we have identified a SNP (rs10507391) in ALOX5 gene, previously associated with an increased risk of stroke, as a novel genetic risk factor for AD. ALOX5 gene encodes a 5'-lipoxygenase (5'-LO) activating protein (FLAP), a crucial component of the arachidonic acid/leukotriene inflammatory cascade. A-allele of rs4769874 polymorphism increases the risk of AD 1.41-fold (p<0.0001), while AA genotype does so 1.79-fold (p<0.0001). In addition, GG genotype of rs4769874 polymorphism is associated with a modest increase in body mass index (BMI). We discuss potential biochemical mechanisms linking the SNP to AD and suggest possible preventive pharmacotherapies some of which are based on commonly available natural products. Finally, we set the newly identified AD risk factors into a broader context of similar CVD risk factors to generate a more comprehensive picture of interacting genetics and life-style habits potentially leading to the deteriorating mental health in the old age.