Role of genes GSTM1, GSTT1, and MnSOD in the development of late-onset Alzheimer disease and their relationship with APOE*4

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Salazar Alcalá, M. Fernández-Mestre" "autores" => array:3 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "de Mendonça" ] 1 => array:2 [ "nombre" => "E." "apellidos" => "Salazar Alcalá" ] 2 => array:4 [ "nombre" => "M." "apellidos" => "Fernández-Mestre" "email" => array:2 [ 0 => "mfernandezmestre@gmail.com" 1 => "mfernand@ivic.gob.ve" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Papel de las variantes GSTM1, GSTT1 y MnSOD en el desarrollo de enfermedad de Alzheimer de aparición tardía y su relación con el alelo 4 de APOE" ] ] "textoCompleto" => "IntroductionNeurodegenerative diseases, including Alzheimer disease (AD), display oxidative damage as a common feature, but it is unclear whether this process is the cause or the effect of the disease.<a class="elsevierStyleCrossRef" href="#bib0215">1</a> Oxidative damage may be caused by the peptide amyloid β (Aβ) and the paired helical filaments of tau protein that constitute the typical lesions in AD. The Aβ peptide has been observed to give rise to free radicals<a class="elsevierStyleCrossRef" href="#bib0220">2</a> and inhibit the cytochrome oxidase enzyme. This contributes to oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0225">3</a> Observations have also shown that the paired helical filaments of tau protein may form advanced glycation end-products, and this generates enough reactive oxygen species (ROS) to cause oxidative damage.<a class="elsevierStyleCrossRef" href="#bib0230">4</a> Since the brain is a major consumer of oxygen with a high demand for energy and only limited antioxidant ability compared to other tissues, it is very susceptible to oxidative damage. Antioxidant defences therefore play a vital role as the means of eliminating free radicals.<a class="elsevierStyleCrossRef" href="#bib0235">5</a> Patients with AD have displayed altered activity of glutathione S-transferase enzymes (GSTs) and manganese superoxide dismutase (MnSOD).<a class="elsevierStyleCrossRef" href="#bib0240">6</a> GSTs are a family of enzymes that are crucial to the protection of cells against toxic substances and oxidative stress. They are encoded by some 16 genes, further subdivided into 8 classes.<a class="elsevierStyleCrossRef" href="#bib0245">7</a> The μ class comprises 5 different isoenzymes named GSTM1 through GSTM5. The θ class includes only 2 isoenzymes, GSTT1 and GSTT2. The null genotypes of genes GSTM1 and GSTT1 are characterised by homozygous knockout of the gene, resulting in absent enzyme activity (overview by Cooper<a class="elsevierStyleCrossRef" href="#bib0250">8</a>). Both the GSTT1 and GSTM1 enzymes are known for their ability to catalyse the detoxification of reactive oxygen and products of lipid peroxidation.<a class="elsevierStyleCrossRef" href="#bib0255">9</a> Because of this, inactivity of the GSTT1/M1 enzymes has been linked to greater exposure to oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0260">10</a>The superoxide dismutase enzyme (SOD) is one of the main defences against the damage that can be caused by the free radical superoxide (O2−). The enzyme catalyses the conversion of superoxide into molecular oxygen (O2) and hydrogen peroxide (H2O2); these molecules will later be converted into water by the action of catalase or glutathione peroxidase enzymes.<a class="elsevierStyleCrossRef" href="#bib0265">11</a> Superoxide dismutase exists in 3 isoforms: cytosolic [Cu/ZnSOD], extracellular [EC-SOD], and mitochondrial [MnSOD].<a class="elsevierStyleCrossRef" href="#bib0270">12</a> Since 90% of all ROS originate in the mitochondria, MnSOD is an antioxidant which plays a fundamental role in protecting cells against oxidative stress. The activity of this mitochondrial enzyme defends cells from lipid peroxidation; within the brain, it protects the viability of the neuronal membrane.<a class="elsevierStyleCrossRef" href="#bib0275">13</a> MnSOD enzyme is synthesised in the cytosol and then transported to the mitochondria. MnSOD transport requires the participation of a sequence of 24 amino acids known as the mitochondrial targeting sequence (MTS). These amino acids form the amphiphilic helices required to transport the enzyme to the mitochondria.<a class="elsevierStyleCrossRef" href="#bib0280">14</a> The gene that encodes MnSOD possesses a polymorphism by which thymine (T) is replaced by cytosine (C) at nucleotide 47, resulting in an amino acid substitution (Val→Ala) at position −9 of the MTS and altering the enzyme structure. These changes in the structure alter mitochondrial transport of MnSOD, and therefore affect the cell's ability to defend itself from superoxide.<a class="elsevierStyleCrossRef" href="#bib0280">14</a> Multiple studies have now demonstrated the role MnSOD plays in how neurons survive oxidative stress.<a class="elsevierStyleCrossRefs" href="#bib0285">15,16</a> Considering that GSTT1, GSTM1, and MnSOD enzymes contribute to cell defence against oxidative stress, and the possibility that oxidative stress and AD pathogenesis are related, we aim to study the role of polymorphisms of the genes GSTT1, GSTM1 and MnSOD in the development of AD and correlate any such associations with the presence of allele ¿4 of the APOE gene.Materials and methodsPatientsThe study was carried out in 79 patients (mean age, 70±10 years), all of whom had been diagnosed with sporadic AD. All patients had received treatment in the neurology department at Hospital Clínico Universitario de Caracas (Venezuela) at some time between September 2004 and October 2006. These patients were selected according to the clinical protocol implemented in the Luis Borges Neuropsychology Unit of the neurology department at Hospital Clínico Universitario de Caracas. The protocol was framed in accordance with the specifications of the American Psychiatric Association (DSM-IV) and the NINCDS-ADRDA Alzheimer's Criteria (National Institute of Neurological Disorders, Communicative Disorders, and Stroke; Alzheimer's Disease and Related Disorders Association).The control group consisted of 100 healthy Venezuelan residents with a mean age of 71±10 years. These subjects completed the Mini-Mental State Examination and laboratory and imaging studies.All participants in the study gave their informed consent; the consent of participants with AD was authorised by their legal guardians. The consent procedure was approved by the bioethics committees at Instituto Venezolano de Investigaciones Científicas and Hospital Clínico Universitario de Caracas.Genomic DNA extractionGenomic DNA was extracted from leukocytes and lymphocytes in peripheral blood according to Bunce's method.<a class="elsevierStyleCrossRef" href="#bib0295">17</a>Detection of GSTT1/GSTM1 genesA multiplex PCR protocol was used to determine presence or absence of the GSTM1 and GSTT1 genes according to a modified version of the method described by Lin et al.<a class="elsevierStyleCrossRef" href="#bib0300">18</a> and the specific initiators used by Chen et al.<a class="elsevierStyleCrossRef" href="#bib0305">19</a>Genotyping of the MnSOD geneThe Ala-9Val polymorphism was studied using the PCR-RFLP method with the initiators and protocol described by Ambrosone et al.<a class="elsevierStyleCrossRef" href="#bib0310">20</a>Genotyping of the APOE geneResearchers genotyped and evaluated the APOE polymorphism using PCR-RFLP with the initiators described by Emi et al.<a class="elsevierStyleCrossRef" href="#bib0315">21</a> and the protocol published by Hixson and Vernier.<a class="elsevierStyleCrossRef" href="#bib0320">22</a>Statistical analysisGenotypic and allelic frequencies were calculated. The statistical significance of intergroup differences in frequency (for alleles, genotypes, and genotypic combinations) was estimated using the Mantel–Haenszel chi-square statistic and 2×2 contingency tables. Researchers adjusted P-values by multiplying them by the number of completed comparisons (Bonferroni correction). Differences were considered statistically significant for P<.05.ResultsGenotype distribution and genotypic combination of GSTT1 and GSTM1 genes in healthy individuals and patients with Alzheimer disease<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> displays the distribution of the GSTM1 (wild-type [+], null [−]) and GSTT1 (wild-type [+], null [−]) in healthy individuals and patients with AD. The comparison of frequencies revealed the wild-type GSTM1 genotype to be significantly more frequent in controls than in patients (OR: 0.58; 95% CI: 0.3235-1.0659; P=.04; Pcorr=ns). In contrast, the null GSTM1 genotype had a significantly higher frequency in patients than in controls (OR: 1.7; 95% CI: 0.9381-3.0903; P=.04; Pcorr=ns). Nevertheless, differences were not statistically significant once P-values were corrected.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The study of genotype combinations for GSTT1 and GSTM1 found that all possible combinations were present in both groups. The GSTT1+/GSTM1− combination was the most frequent in patients with AD, followed by the combinations GSTT1+/GSTM1+, GSTT1−/GSTM1+, and GSTT1−/GSTM1−. The GSTT1+/GSTM1+ combination was the most frequent among healthy controls, followed by the combinations GSTT1+/GSTM1−, GSTT1−/GSTM1+, and GSTT1−/GSTM1−. The comparison of frequencies revealed the combination GSTT1+/GSTM1− to be significantly more frequent in patients than in controls (OR: 2.06; 95% CI: 1.1118-3.8036; P=.09; Pcorr=.036). The P-value remained significant after correction (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Allelic and genotypic frequencies of the MnSOD gene in healthy individuals and patients with Alzheimer diseaseIn both groups, the Ala/Val genotype had the highest frequency, followed by Ala/Ala and Val/Val in AD patients and Val/Val and Ala/Ala in healthy controls. The comparison of frequencies revealed the Ala/Val genotype to be significantly more frequent in patients than in controls (OR: 1.9; 95% CI: 0.9147-3.9498; P=.04; Pcorr=ns). However, differences were not statistically significant once P-values were corrected (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Allelic and genotypic frequency distributions of the MnSOD gene in healthy individuals and patients with Alzheimer disease<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> displays the genotypes of the APOE gene for AD patients and healthy controls. The frequencies of genotypes ¿2¿3 (OR=0.04; 95% CI: 0.002-0.764; P=.0007; Pcorr=.0035) and ¿3¿3 (OR=0.55; IC 95%: 0.3073-1.0136; P=.02; Pcorr=ns) were significantly higher in controls than in AD patients. In contrast, patients displayed higher frequencies of genotypes ¿3¿4 (OR=1.93; 95% CI: 1.0164-3.6980; P=.02; Pcorr=ns) and ¿4¿4 (OR=4.29; 95% CI: 1.3241-13.9016; P=.004; Pcorr=.02). The comparison of allele frequencies also showed that ¿2 (OR=0.04; 95% CI: 0.0059-0.3651; P=.000025; Pcorr=.000075) and allele ¿3 (OR=0.5; 95% CI: 0.3220-0.8195; P=.0024; Pcorr=.0072) were significantly more common among controls than in AD patients. Nevertheless, allele ¿4 was significantly more frequent in AD patients than in controls (OR=2.8; 95% CI: 1.7003-4.6221; P=.000019; Pcorr=.000057).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Study of the combined effect of polymorphism in GSTT1, GSTM1 and APOE genesThere are 24 possible combinations of GSTT1/GSTM1/APOE, and we observed 11 in the AD group and 15 in the controls. The frequencies of the combinations GSTT1+/GSTM1+/¿2¿3 (OR=0.1; 95% CI: 0.0059-2.004; P=.02; Pcorr=ns) and GSTT1+/GSTM1+/¿3¿3 (OR=0.46; 95% CI: 0.2114-1.002; P=.02; Pcorr=ns) were significantly higher in controls than in patients. In contrast, frequencies of the combinations GSTT1+/GSTM1−/¿3¿4 (OR=3.07; 95% CI: 1.0210-9.2514; P=.019; Pcorr=ns) and GSTT1+/GSTM1−/¿4¿4 (OR=5.52; 95% CI: 1.1381-26.7837; P=.009; Pcorr=ns) were significantly higher in AD patients than in controls (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Study of the combined effect of the polymorphism Ala-9Val in the genes MnSOD and APOEOf the 18 possible combinations of MnSOD/APOE, 12 were observed in controls and 9 in patients. The combinations AlaAla/¿3¿4 (OR=3.4; 95% CI: 1.0476-11.5486; P=.016; Pcorr=ns) and AlaVal/¿4¿4 (OR=7.9; 95% CI: 1.7027-36.8988; P=.001; Pcorr=ns) were significantly more common in AD patients than in controls. We must point out that some genotype combinations were present only in the control group: AlaVal/¿2¿3 (OR=0.09; 95% CI: 0.0050-1.6480; P=.014; Pcorr=ns), AlaVal/¿3¿3 (OR=0.5; 95% CI: 0.2642-0.9461; P=.016; Pcorr=ns), and ValVal/¿2¿3 (OR=0.1; 95% CI: 0.0059-2.0049; P=.02; Pcorr=ns) (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>DiscussionThe imbalance between the production and the elimination of ROS and nitrogen is known as oxidative stress. The cell must overcome oxidative stress to restore redox balance and thereby avoid the neuronal death and loss of neuronal function that are associated with neurodegenerative diseases.<a class="elsevierStyleCrossRef" href="#bib0325">23</a> Studies in the area of AD pathogenesis have focused on the role of oxidative stress since the central nervous system is a great consumer of energy with only minimal antioxidant defences, making it highly sensitive to oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0330">24</a> In the brain with AD, antioxidant systems function less effectively, which may lead to an increase in the reactive species of oxygen and nitrogen that would react to biomolecules, including proteins, lipids, carbohydrates, DNA, and RNA. This would cause changes in their chemical structure, and in turn, loss of function.<a class="elsevierStyleCrossRef" href="#bib0335">25</a> Oxidative stress in the brains of AD patients is well-documented: researchers have observed high levels of antioxidant enzymes, as well as increased concentrations of oxidative stress markers in the brains of AD patients compared to those of age-matched controls. Furthermore, the role played by oxidative stress in AD progression was observed when we compared the presence of the same brain proteins with oxidative damage in subjects with mild cognitive impairment, early-stage AD, and late-stage AD. This demonstrates that certain major pathways are activated and may be involved in AD progression.<a class="elsevierStyleCrossRef" href="#bib0335">25</a> Given that the GST family of enzymes conjugates reduced glutathione with electrophilic compounds, thus helping remove it from cells to prevent oxidative damage,<a class="elsevierStyleCrossRef" href="#bib0340">26</a> several studies have been published on the genes that encode the GSTM1 and GSTT1 enzymes and their role in different diseases. These enzymes proceed from a null phenotype characterised by absence of enzymatic activity due to inherited homozygous elimination of the full gene. In this study, the null GSTM1 genotype was significantly more frequent in patients with AD (OR: 1.7; P=.04; Pcorr=ns); the wild-type GSTM1 genotype was significantly more common in healthy controls (OR=0.58; P=.04; Pcorr=ns), in contrast with findings from other studies.<a class="elsevierStyleCrossRefs" href="#bib0255">9,27–30</a> Likewise, the combination GSTT1+/GSTM1− was more frequently seen in AD patients than in controls (OR: 2.06; Pcorr=.036). These results suggest that the null genotype GSTM1 and the combination GSTT1+/GSTM1− could confer up to twice the risk of developing AD. Considering that a variety of studies suggest that variations in the APOE gene may be genetic risk factors for AD,<a class="elsevierStyleCrossRefs" href="#bib0365">31–33</a> we recorded the combinations of GSTT1/GSTM1 and APOE genotypes and obtained interesting results. The genotype combinations GSTT1+/GSTM1−/¿3¿4 and GSTT1+/GSTM1−/¿4¿4 were significantly more frequent in patients than in controls. These combinations may therefore be linked to increased likelihood of developing AD. Additionally, the risk posed by the presence of one or 2 ¿4 alleles of the APOE gene is higher in the combination in which the GSTM1 gene is absent. Considering the above, an increase in Aβ peptide aggregation due to the E4 isoform of apolipoprotein E,<a class="elsevierStyleCrossRef" href="#bib0380">34</a> together with the reduction in antioxidant defences caused by homozygotic elimination of the GSTM1 gene, could generate greater oxidative stress. This in turn would give rise to more neuronal death and explain how the risk inherent to allele ¿4 of the APOE gene would multiply in the absence of the GSTM1 gene. Furthermore, combinations including wild-type GSTT1 and GSTM1 and at least one ¿3 allele [GSTT1+/GSTM1+/¿2¿3 and GSTT1+/GSTM1+/¿3¿3] were significantly more frequent in healthy controls than in AD patients. This suggests that these combinations may provide protection against the onset of AD. Aβ peptides are components of the senile plaques that begin degeneration of brain neurons in AD by increasing the presence of ROS until it exceeds the defence ability of each cell. Kaminsky and Kosenko<a class="elsevierStyleCrossRef" href="#bib0385">35</a> studied the effects of Aβ peptides on antioxidant enzymes from mitochondrial and non-mitochondrial sources in the rat brain in vivo. They observed that Aβ peptides increase the enzymatic activities creating H2O2 while inhibiting the activity of enzymes that consume H2O2 in the mitochondria and cytosol. This finding suggests that the imbalance between enzymes generating and those metabolising H2O2 contribute to the underlying oxidative stress in the neurodegeneration and neuronal death that occur in AD. Furthermore, the Aβ peptide has been found to be involved in the decreased expression of cytochrome c oxidase in the mitochondria, which in turn affects the electron transport chain and produces ROS.<a class="elsevierStyleCrossRef" href="#bib0225">3</a> The MnSOD enzyme forms part of the cell's enzymatic antioxidant defences, and in fact provides the cell's first line of defence against the superoxide anion by converting it into H2O2.<a class="elsevierStyleCrossRef" href="#bib0270">12</a> Multiple studies now support that MnSOD plays a role in how neurons survive oxidative stress. One such study, performed in MnSOD gene-knockout mice, reported that the mice died not long after birth with signs of neurodegeneration.<a class="elsevierStyleCrossRefs" href="#bib0285">15,16</a> Similarly, studies in transgenic rats have reported that MnSOD deficiency increases the concentrations of the Aβ peptide, which favours the formation of senile plaques.<a class="elsevierStyleCrossRef" href="#bib0390">36</a> However, other studies have reported that overexpression of the MnSOD enzyme actually protects neurons from oxidative damage.<a class="elsevierStyleCrossRefs" href="#bib0395">37–39</a> In light of this conflicting evidence, we studied the Ala-9Val polymorphism of the MnSOD gene that alters the secondary structure of that protein, and therefore the mitochondrial transport of MnSOD. This affects the cell's ability to defend itself from superoxide radicals.<a class="elsevierStyleCrossRef" href="#bib0410">40</a> A comparison of the frequencies of the Ala-9Val genotypes of MnSOD showed that genotype Ala/Ala was significantly more frequent in patients than in healthy controls. This finding does not coincide with the results from an Italian population reported by Ventriglia et al.<a class="elsevierStyleCrossRef" href="#bib0275">13</a> Furthermore, evaluating the combined effect of the MnSOD and APOE genes revealed that the frequencies of the combinations AlaAla/¿3¿4 (OR=3.4; P=.03) and AlaVal/¿4¿4 (OR=7.9; P=.01) were significantly higher in patients than in controls, meaning that these combinations may indicate a greater susceptibility to AD. The presence of the Ala allele, which is associated with greater enzymatic activity of MnSOD in humans, as well as the presence of allele ¿4, promotes the development of AD. We should point out that the risk associated with genotypes ¿3¿4 and ¿4¿4 (OR=1.93 and OR=4.29, respectively) is approximately twice as high when the genotypes AlaAla and AlaVal of the MnSOD gene are present (OR=3.4 and OR=7.9, respectively). In contrast, the genotypic combinations AlaVal/¿2¿3, AlaVal/¿3¿3, and ValVal/¿2¿3 were only present in healthy individuals. This suggests that they may play a protective role against AD. Allele ¿3, whether present homozygously or with allele ¿2, together with one or 2 doses of the Val allele that is associated with abnormal enzymatic activity by MnSOD,<a class="elsevierStyleCrossRefs" href="#bib0410">40,41</a> would therefore protect individuals from developing AD. Considering that the Ala form of MnSOD is more efficiently transported to the mitochondria than the Val form,<a class="elsevierStyleCrossRef" href="#bib0280">14</a> and that this enzyme catalyses the dismutation of the superoxide anion in H2O2 so that it can subsequently be removed from the mitochondria by the action of catalase and glutathione peroxidase, researchers have suggested that the increased enzymatic activity of MnSOD would result in more production of H2O2. This in turn would create an imbalance between H2O2 generation and metabolism that would promote oxidative stress and damage within the cell. Such an imbalance might be due to reduced activity of the enzymes contributing to H2O2 elimination, such as catalase and glutathione peroxidase.<a class="elsevierStyleCrossRefs" href="#bib0385">35,42</a> The results support the hypothesis that deterioration of the mitochondrial function and increased oxidative damage are involved in AD pathogenesis. It is important, nonetheless, to point out that other genes linked to oxidative stress and antioxidant pathways may also affect susceptibility to developing AD, and that their genetic variability should therefore be studied.Conflict of interestThe authors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres735095" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec738832" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres735096" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec738831" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Genomic DNA extraction" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Detection of GSTT1/GSTM1 genes" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Genotyping of the MnSOD gene" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Genotyping of the APOE gene" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Genotype distribution and genotypic combination of GSTT1 and GSTM1 genes in healthy individuals and patients with Alzheimer disease" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Allelic and genotypic frequencies of the MnSOD gene in healthy individuals and patients with Alzheimer disease" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Allelic and genotypic frequency distributions of the MnSOD gene in healthy individuals and patients with Alzheimer disease" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Study of the combined effect of polymorphism in GSTT1, GSTM1 and APOE genes" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Study of the combined effect of the polymorphism Ala-9Val in the genes MnSOD and APOE" ] ] ] 7 => array:2 [ "identificador" => "sec0075" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-05-03" "fechaAceptado" => "2014-10-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec738832" "palabras" => array:6 [ 0 => "Polymorphism" 1 => "Alzheimer disease" 2 => "GSTM1" 3 => "GSTT1" 4 => "MnSOD" 5 => "Oxidative damage" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec738831" "palabras" => array:6 [ 0 => "Polimorfismo" 1 => "Alzheimer" 2 => "GSTM1" 3 => "GSTT1" 4 => "MnSOD" 5 => "Daño oxidativo" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionSeveral studies have reported increased oxidation of lipids, proteins and DNA in the brains of patients with Alzheimer disease (AD). Moreover, these patients display differences in the activity and polymorphisms of the genes encoding the enzymes GST (T1, M1) and MnSOD. For these reasons, we designed a study of the variability in GSTT1, GSTM1, and MnSOD genes in healthy and AD groups from a Venezuelan population. MethodsWe included 179 unrelated Venezuelan subjects classified as either AD patients (n=79) or healthy individuals (n=100). Presence or absence of the GSTT1/GSTM1 genes was determined using PCR-SSP, and polymorphisms of MnSOD and APOE genes were identified with PCR-RFLP. ResultsThe genotype GSTT1+/GSTM1− seems to favour development of AD (OR=2.06, P=.01). The risk level is higher when it is combined with the ¿4 allele of the APOE gene: GSTT1+/GSTM1−/¿3¿4 (OR=3.07, P=.05), GSTT1+/GSTM1−/¿4¿4 (OR=5.52, P=.02). The Ala-9Val polymorphism does not appear to be related to AD. However, the presence of the Ala/Ala genotype increases the risk provided by the ¿4 allele of the APOE gene: AlaAla/¿3¿4 (OR=3.47, P=.03), AlaAla/¿4¿4 (OR=6.3, P=.01). ConclusionsThe results support the hypothesis that impaired mitochondrial function and increased oxidative damage are involved in the pathogenesis of AD. It is important to study other genes related to oxidative stress and antioxidant pathways which could be involved in susceptibility to AD." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónDiversos estudios han descrito que en los cerebros de pacientes con enfermedad de Alzheimer (EA) hay una mayor oxidación de lípidos, proteínas y ADN. Además, en estos pacientes se ha observado diferencias en la actividad y polimorfismos de los genes que codifican las enzimas GST (T1 y M1) y MnSOD. En virtud de ello se planteó estudiar la variabilidad de los genes GSTT1, GSTM1 y MnSOD en individuos venezolanos sanos y con EA. MétodosSe incluyeron 179 individuos venezolanos, no relacionados, agrupados en pacientes con EA (n=79) e individuos sanos (n=100). La presencia o ausencia de los genes GSTT1/GSTM1 se determinó por PCR-SSP y los polimorfismo de los genes MnSOD y APOE por PCR-RFLP. ResultadosEl genotipo GSTT1+/GSTM1− parece favorecer el desarrollo de la EA (OR=2,06; p=0,01), siendo el riesgo mayor al estar en combinación con el alelo ¿4 del gen APOE: GSTT1+/GSTM1−/¿3¿4 (OR=3,07; p=0,05), GSTT1+/GSTM1−/¿4¿4 (OR=5,52; p=0,02). El polimorfismo Ala-9Val por sí solo no parece estar relacionado con la EA, sin embargo, la presencia del genotipo Ala/Ala incrementa el riesgo que proporciona el alelo ¿4 del gen APOE: AlaAla/¿3¿4 (OR=3,47; p=0,03), AlaAla/¿4¿4 (OR=6,3; p=0,01). ConclusionesLos resultados apoyan la hipótesis de que el deterioro de la función mitocondrial y el aumento de daño oxidativo están involucrados en la patogénesis de la EA. Es importante estudiar otros genes relacionados con estrés oxidativo y vías antioxidantes, los cuales pudiesen estar involucrados en la susceptibilidad a desarrollar la EA." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: de Mendonça E, Salazar Alcalá E, Fernández-Mestre M. Papel de las variantes GSTM1, GSTT1 y MnSOD en el desarrollo de enfermedad de Alzheimer de aparición tardía y su relación con el alelo 4 de APOE. Neurología. 2016;31:535–542." ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD: Alzheimer disease; 95% CI: confidence interval; ns: not significant; OR: odds ratio.Values shown in parentheses indicate the number of individuals bearing the genotype for the polymorphic site under study. Frequencies are expressed as percentages.* Significant after applying the Bonferroni correction." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD n=79 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy n=100 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR 95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">GSTT1 alleles</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wild-type (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83.5 (66) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78 (78) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Null (−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16.5 (13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 (22) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">GSTM1 alleles</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wild-type (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46.8 (37) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 (60) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.04 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Null (−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.2 (42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 (40) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.04 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Allele combinations</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1+ GSTM1− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35.4 (28) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 (47) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.08 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1− GSTM1− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.1 (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1+ GSTM1− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48.1 (38) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 (31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.009* \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1− GSTM1+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.4 (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 (13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1213264.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Distribution of genotypes and genotype combinations for the genes GSTT1 and GSTM1 in patients with AD and healthy controls." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD: Alzheimer disease; 95% CI: confidence interval; ns: not significant; OR: odds ratio.Values shown in parentheses indicate the number of repeats of the allele or the number of individuals bearing the genotype for the polymorphic site under study. Frequencies are expressed as percentages." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD n=79 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy n=100 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR 95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Genotypes</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ala/Ala \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.6 (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 (16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.04 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ala/Val \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54.4 (43) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63 (63) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Val/Val \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 (15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Alleles</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ala \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.8 (85) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47.5 (95) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Val \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">46.2 (73) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52.5 (105) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1213263.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Allelic and genotypic frequency of the Ala-9Val polymorphism of the MnSOD gene in patients and controls." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD: Alzheimer disease; 95% CI: confidence interval; ns: not significant; OR: odds ratio.Values in parentheses indicate the number of individuals bearing the genotype. Frequencies are expressed as percentages." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD n=79 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls n=100 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR 95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Genotype</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿2/¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.0007 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿2/¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.3 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.84 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ns \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿3/¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">45.6 (36) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 (60) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿3/¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">37.9 (30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 (24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿4/¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15.2 (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.004 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Alleles</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.00002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">64.6 (102) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78 (156) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.513 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.0024 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">34.8 (55) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16 (32) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.000019 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1213265.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Frequencies of genotypes and alleles of the APOE gene in patients with AD and controls." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD: Alzheimer disease; 95% CI: confidence interval; OR: odds ratio; χ2: chi-square test.Values in parentheses indicate the number of individuals bearing the genotype. Frequencies are expressed as percentages." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD n=79 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls n=100 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR 95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P (χ2) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Genotype</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1+/GSTM1+/¿2¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1+/GSTM1+/¿3¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 (26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1+/GSTM1−/¿3¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.019 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GSTT1+/GSTM1−/¿4¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.009 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1213262.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Frequencies of genotype combinations for GSTT1/GSTM1/APOE in patients with AD and controls." ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD: Alzheimer disease; 95% CI: confidence interval; OR: odds ratio; χ2: chi-square test.Values in parentheses show the number of individuals bearing the genotype for the polymorphic site under study. Frequencies are expressed as percentages." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD n=79 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls n=100 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR 95% CI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">P (χ2) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Genotype</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AlaAla/¿3¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.6 (10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AlaVal/¿2¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AlaVal/¿3¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.6 (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 (42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.02 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AlaVal/¿4¿4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.4 (9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ValVal/¿2¿3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.05 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1213266.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Frequencies of genotype combinations of the MnSOD/APOE gene in patients with AD and controls." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:42 [ 0 => array:3 [ "identificador" => "bib0215" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estrés oxidativo y neurodegeneración" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C. 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Papel de las variantes GSTM1, GSTT1 y MnSOD en el desarrollo de enfermedad de Alzheimer de aparición tardía y su relación con el alelo 4 de APOE

E. de Mendonça, E. Salazar Alcalá, M. Fernández-Mestre

Corresponding author

mfernandezmestre@gmail.com
mfernand@ivic.gob.ve

Corresponding author.

Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Neurodegenerative diseases&#44; including Alzheimer disease &#40;AD&#41;&#44; display oxidative damage as a common feature&#44; but it is unclear whether this process is the cause or the effect of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">1</span></a> Oxidative damage may be caused by the peptide amyloid &#946; &#40;A&#946;&#41; and the paired helical filaments of tau protein that constitute the typical lesions in AD&#46; The A&#946; peptide has been observed to give rise to free radicals<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">2</span></a> and inhibit the cytochrome oxidase enzyme&#46; This contributes to oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">3</span></a> Observations have also shown that the paired helical filaments of tau protein may form advanced glycation end-products&#44; and this generates enough reactive oxygen species &#40;ROS&#41; to cause oxidative damage&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">4</span></a> Since the brain is a major consumer of oxygen with a high demand for energy and only limited antioxidant ability compared to other tissues&#44; it is very susceptible to oxidative damage&#46; Antioxidant defences therefore play a vital role as the means of eliminating free radicals&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">5</span></a> Patients with AD have displayed altered activity of glutathione S-transferase enzymes &#40;GSTs&#41; and manganese superoxide dismutase &#40;MnSOD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">6</span></a> GSTs are a family of enzymes that are crucial to the protection of cells against toxic substances and oxidative stress&#46; They are encoded by some 16 genes&#44; further subdivided into 8 classes&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">7</span></a> The &#956; class comprises 5 different isoenzymes named GSTM1 through GSTM5&#46; The &#952; class includes only 2 isoenzymes&#44; GSTT1 and GSTT2&#46; The null genotypes of genes <span class="elsevierStyleItalic">GSTM1</span> and <span class="elsevierStyleItalic">GSTT1</span> are characterised by homozygous knockout of the gene&#44; resulting in absent enzyme activity &#40;overview by Cooper<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">8</span></a>&#41;&#46; Both the GSTT1 and GSTM1 enzymes are known for their ability to catalyse the detoxification of reactive oxygen and products of lipid peroxidation&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">9</span></a> Because of this&#44; inactivity of the GSTT1&#47;M1 enzymes has been linked to greater exposure to oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">10</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The superoxide dismutase enzyme &#40;SOD&#41; is one of the main defences against the damage that can be caused by the free radical superoxide &#40;O<span class="elsevierStyleSup">2&#8722;</span>&#41;&#46; The enzyme catalyses the conversion of superoxide into molecular oxygen &#40;O<span class="elsevierStyleInf">2</span>&#41; and hydrogen peroxide &#40;H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>&#41;&#59; these molecules will later be converted into water by the action of catalase or glutathione peroxidase enzymes&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">11</span></a> Superoxide dismutase exists in 3 isoforms&#58; cytosolic &#91;Cu&#47;ZnSOD&#93;&#44; extracellular &#91;EC-SOD&#93;&#44; and mitochondrial &#91;MnSOD&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">12</span></a> Since 90&#37; of all ROS originate in the mitochondria&#44; MnSOD is an antioxidant which plays a fundamental role in protecting cells against oxidative stress&#46; The activity of this mitochondrial enzyme defends cells from lipid peroxidation&#59; within the brain&#44; it protects the viability of the neuronal membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">13</span></a> MnSOD enzyme is synthesised in the cytosol and then transported to the mitochondria&#46; MnSOD transport requires the participation of a sequence of 24 amino acids known as the mitochondrial targeting sequence &#40;MTS&#41;&#46; These amino acids form the amphiphilic helices required to transport the enzyme to the mitochondria&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">14</span></a> The gene that encodes MnSOD possesses a polymorphism by which thymine &#40;T&#41; is replaced by cytosine &#40;C&#41; at nucleotide 47&#44; resulting in an amino acid substitution &#40;Val&#8594;Ala&#41; at position &#8722;9 of the MTS and altering the enzyme structure&#46; These changes in the structure alter mitochondrial transport of MnSOD&#44; and therefore affect the cell&#39;s ability to defend itself from superoxide&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">14</span></a> Multiple studies have now demonstrated the role MnSOD plays in how neurons survive oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">15&#44;16</span></a> Considering that GSTT1&#44; GSTM1&#44; and MnSOD enzymes contribute to cell defence against oxidative stress&#44; and the possibility that oxidative stress and AD pathogenesis are related&#44; we aim to study the role of polymorphisms of the genes <span class="elsevierStyleItalic">GSTT1&#44; GSTM1</span> and <span class="elsevierStyleItalic">MnSOD</span> in the development of AD and correlate any such associations with the presence of allele ¿4 of the <span class="elsevierStyleItalic">APOE</span> gene&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0015" class="elsevierStylePara elsevierViewall">The study was carried out in 79 patients &#40;mean age&#44; 70<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10 years&#41;&#44; all of whom had been diagnosed with sporadic AD&#46; All patients had received treatment in the neurology department at Hospital Cl&#237;nico Universitario de Caracas &#40;Venezuela&#41; at some time between September 2004 and October 2006&#46; These patients were selected according to the clinical protocol implemented in the Luis Borges Neuropsychology Unit of the neurology department at Hospital Cl&#237;nico Universitario de Caracas&#46; The protocol was framed in accordance with the specifications of the American Psychiatric Association &#40;DSM-IV&#41; and the NINCDS-ADRDA Alzheimer&#39;s Criteria &#40;National Institute of Neurological Disorders&#44; Communicative Disorders&#44; and Stroke&#59; Alzheimer&#39;s Disease and Related Disorders Association&#41;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The control group consisted of 100 healthy Venezuelan residents with a mean age of 71<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10 years&#46; These subjects completed the Mini-Mental State Examination and laboratory and imaging studies&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">All participants in the study gave their informed consent&#59; the consent of participants with AD was authorised by their legal guardians&#46; The consent procedure was approved by the bioethics committees at Instituto Venezolano de Investigaciones Cient&#237;ficas and Hospital Cl&#237;nico Universitario de Caracas&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Genomic DNA extraction</span><p id="par0030" class="elsevierStylePara elsevierViewall">Genomic DNA was extracted from leukocytes and lymphocytes in peripheral blood according to Bunce&#39;s method&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Detection of <span class="elsevierStyleItalic">GSTT1</span>&#47;<span class="elsevierStyleItalic">GSTM1</span> genes</span><p id="par0035" class="elsevierStylePara elsevierViewall">A multiplex PCR protocol was used to determine presence or absence of the <span class="elsevierStyleItalic">GSTM1</span> and <span class="elsevierStyleItalic">GSTT1</span> genes according to a modified version of the method described by Lin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">18</span></a> and the specific initiators used by Chen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Genotyping of the <span class="elsevierStyleItalic">MnSOD</span> gene</span><p id="par0040" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Ala-9Val</span> polymorphism was studied using the PCR-RFLP method with the initiators and protocol described by Ambrosone et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Genotyping of the <span class="elsevierStyleItalic">APOE</span> gene</span><p id="par0045" class="elsevierStylePara elsevierViewall">Researchers genotyped and evaluated the <span class="elsevierStyleItalic">APOE</span> polymorphism using PCR-RFLP with the initiators described by Emi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">21</span></a> and the protocol published by Hixson and Vernier&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Genotypic and allelic frequencies were calculated&#46; The statistical significance of intergroup differences in frequency &#40;for alleles&#44; genotypes&#44; and genotypic combinations&#41; was estimated using the Mantel&#8211;Haenszel chi-square statistic and 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 contingency tables&#46; Researchers adjusted <span class="elsevierStyleItalic">P</span>-values by multiplying them by the number of completed comparisons &#40;Bonferroni correction&#41;&#46; Differences were considered statistically significant for <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Genotype distribution and genotypic combination of <span class="elsevierStyleItalic">GSTT1</span> and <span class="elsevierStyleItalic">GSTM1</span> genes in healthy individuals and patients with Alzheimer disease</span><p id="par0055" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> displays the distribution of the <span class="elsevierStyleItalic">GSTM1</span> &#40;wild-type &#91;&#43;&#93;&#44; null &#91;&#8722;&#93;&#41; and <span class="elsevierStyleItalic">GSTT1</span> &#40;wild-type &#91;&#43;&#93;&#44; null &#91;&#8722;&#93;&#41; in healthy individuals and patients with AD&#46; The comparison of frequencies revealed the wild-type <span class="elsevierStyleItalic">GSTM1</span> genotype to be significantly more frequent in controls than in patients &#40;OR&#58; 0&#46;58&#59; 95&#37; CI&#58; 0&#46;3235-1&#46;0659&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;04&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#46; In contrast&#44; the null <span class="elsevierStyleItalic">GSTM1</span> genotype had a significantly higher frequency in patients than in controls &#40;OR&#58; 1&#46;7&#59; 95&#37; CI&#58; 0&#46;9381-3&#46;0903&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;04&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#46; Nevertheless&#44; differences were not statistically significant once <span class="elsevierStyleItalic">P</span>-values were corrected&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The study of genotype combinations for <span class="elsevierStyleItalic">GSTT1</span> and <span class="elsevierStyleItalic">GSTM1</span> found that all possible combinations were present in both groups&#46; The <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;</span> combination was the most frequent in patients with AD&#44; followed by the combinations <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1</span>&#43;&#44; <span class="elsevierStyleItalic">GSTT1&#8722;&#47;GSTM1</span>&#43;&#44; and <span class="elsevierStyleItalic">GSTT1&#8722;&#47;GSTM1&#8722;</span>&#46; The <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#43;</span> combination was the most frequent among healthy controls&#44; followed by the combinations <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;</span>&#44; <span class="elsevierStyleItalic">GSTT1&#8722;&#47;GSTM1</span>&#43;&#44; and <span class="elsevierStyleItalic">GSTT1&#8722;&#47;GSTM1&#8722;</span>&#46; The comparison of frequencies revealed the combination <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;</span> to be significantly more frequent in patients than in controls &#40;OR&#58; 2&#46;06&#59; 95&#37; CI&#58; 1&#46;1118-3&#46;8036&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;09&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;036&#41;&#46; The <span class="elsevierStyleItalic">P</span>-value remained significant after correction &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Allelic and genotypic frequencies of the <span class="elsevierStyleItalic">MnSOD</span> gene in healthy individuals and patients with Alzheimer disease</span><p id="par0065" class="elsevierStylePara elsevierViewall">In both groups&#44; the <span class="elsevierStyleItalic">Ala&#47;Val</span> genotype had the highest frequency&#44; followed by <span class="elsevierStyleItalic">Ala&#47;Ala</span> and <span class="elsevierStyleItalic">Val&#47;Val</span> in AD patients and <span class="elsevierStyleItalic">Val&#47;Val</span> and <span class="elsevierStyleItalic">Ala&#47;Ala</span> in healthy controls&#46; The comparison of frequencies revealed the <span class="elsevierStyleItalic">Ala&#47;Val</span> genotype to be significantly more frequent in patients than in controls &#40;OR&#58; 1&#46;9&#59; 95&#37; CI&#58; 0&#46;9147-3&#46;9498&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;04&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#46; However&#44; differences were not statistically significant once <span class="elsevierStyleItalic">P</span>-values were corrected &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Allelic and genotypic frequency distributions of the <span class="elsevierStyleItalic">MnSOD</span> gene in healthy individuals and patients with Alzheimer disease</span><p id="par0070" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> displays the genotypes of the <span class="elsevierStyleItalic">APOE</span> gene for AD patients and healthy controls&#46; The frequencies of genotypes <span class="elsevierStyleItalic">¿2¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#59; 95&#37; CI&#58; 0&#46;002-0&#46;764&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0007&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0035&#41; and <span class="elsevierStyleItalic">¿3¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55&#59; IC 95&#37;&#58; 0&#46;3073-1&#46;0136&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; were significantly higher in controls than in AD patients&#46; In contrast&#44; patients displayed higher frequencies of genotypes <span class="elsevierStyleItalic">¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;93&#59; 95&#37; CI&#58; 1&#46;0164-3&#46;6980&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; and <span class="elsevierStyleItalic">¿4¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;29&#59; 95&#37; CI&#58; 1&#46;3241-13&#46;9016&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#46; The comparison of allele frequencies also showed that <span class="elsevierStyleItalic">¿2</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#59; 95&#37; CI&#58; 0&#46;0059-0&#46;3651&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;000025&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;000075&#41; and allele <span class="elsevierStyleItalic">¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#59; 95&#37; CI&#58; 0&#46;3220-0&#46;8195&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0024&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0072&#41; were significantly more common among controls than in AD patients&#46; Nevertheless&#44; allele <span class="elsevierStyleItalic">¿4</span> was significantly more frequent in AD patients than in controls &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;8&#59; 95&#37; CI&#58; 1&#46;7003-4&#46;6221&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;000019&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;000057&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Study of the combined effect of polymorphism in <span class="elsevierStyleItalic">GSTT1</span>&#44; <span class="elsevierStyleItalic">GSTM1</span> and <span class="elsevierStyleItalic">APOE</span> genes</span><p id="par0075" class="elsevierStylePara elsevierViewall">There are 24 possible combinations of <span class="elsevierStyleItalic">GSTT1&#47;GSTM1&#47;APOE</span>&#44; and we observed 11 in the AD group and 15 in the controls&#46; The frequencies of the combinations <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#43;&#47;¿2¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;1&#59; 95&#37; CI&#58; 0&#46;0059-2&#46;004&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; and <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#43;&#47;¿3¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;46&#59; 95&#37; CI&#58; 0&#46;2114-1&#46;002&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; were significantly higher in controls than in patients&#46; In contrast&#44; frequencies of the combinations <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;&#47;¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;07&#59; 95&#37; CI&#58; 1&#46;0210-9&#46;2514&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;019&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; and <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;&#47;¿4¿</span>4 &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;52&#59; 95&#37; CI&#58; 1&#46;1381-26&#46;7837&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;009&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; were significantly higher in AD patients than in controls &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Study of the combined effect of the polymorphism <span class="elsevierStyleItalic">Ala-9Val</span> in the genes <span class="elsevierStyleItalic">MnSOD</span> and <span class="elsevierStyleItalic">APOE</span></span><p id="par0080" class="elsevierStylePara elsevierViewall">Of the 18 possible combinations of <span class="elsevierStyleItalic">MnSOD&#47;APOE</span>&#44; 12 were observed in controls and 9 in patients&#46; The combinations <span class="elsevierStyleItalic">AlaAla&#47;¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;4&#59; 95&#37; CI&#58; 1&#46;0476-11&#46;5486&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;016&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; and <span class="elsevierStyleItalic">AlaVal&#47;¿4¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;9&#59; 95&#37; CI&#58; 1&#46;7027-36&#46;8988&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; were significantly more common in AD patients than in controls&#46; We must point out that some genotype combinations were present only in the control group&#58; <span class="elsevierStyleItalic">AlaVal&#47;¿2¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;09&#59; 95&#37; CI&#58; 0&#46;0050-1&#46;6480&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;014&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#44; <span class="elsevierStyleItalic">AlaVal&#47;¿3¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#59; 95&#37; CI&#58; 0&#46;2642-0&#46;9461&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;016&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#44; and <span class="elsevierStyleItalic">ValVal&#47;¿2¿3</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;1&#59; 95&#37; CI&#58; 0&#46;0059-2&#46;0049&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">The imbalance between the production and the elimination of ROS and nitrogen is known as oxidative stress&#46; The cell must overcome oxidative stress to restore redox balance and thereby avoid the neuronal death and loss of neuronal function that are associated with neurodegenerative diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">23</span></a> Studies in the area of AD pathogenesis have focused on the role of oxidative stress since the central nervous system is a great consumer of energy with only minimal antioxidant defences&#44; making it highly sensitive to oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">24</span></a> In the brain with AD&#44; antioxidant systems function less effectively&#44; which may lead to an increase in the reactive species of oxygen and nitrogen that would react to biomolecules&#44; including proteins&#44; lipids&#44; carbohydrates&#44; DNA&#44; and RNA&#46; This would cause changes in their chemical structure&#44; and in turn&#44; loss of function&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">25</span></a> Oxidative stress in the brains of AD patients is well-documented&#58; researchers have observed high levels of antioxidant enzymes&#44; as well as increased concentrations of oxidative stress markers in the brains of AD patients compared to those of age-matched controls&#46; Furthermore&#44; the role played by oxidative stress in AD progression was observed when we compared the presence of the same brain proteins with oxidative damage in subjects with mild cognitive impairment&#44; early-stage AD&#44; and late-stage AD&#46; This demonstrates that certain major pathways are activated and may be involved in AD progression&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">25</span></a> Given that the GST family of enzymes conjugates reduced glutathione with electrophilic compounds&#44; thus helping remove it from cells to prevent oxidative damage&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">26</span></a> several studies have been published on the genes that encode the GSTM1 and GSTT1 enzymes and their role in different diseases&#46; These enzymes proceed from a null phenotype characterised by absence of enzymatic activity due to inherited homozygous elimination of the full gene&#46; In this study&#44; the null <span class="elsevierStyleItalic">GSTM1</span> genotype was significantly more frequent in patients with AD &#40;OR&#58; 1&#46;7&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;04&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#59; the wild-type <span class="elsevierStyleItalic">GSTM1</span> genotype was significantly more common in healthy controls &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;58&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;04&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#44; in contrast with findings from other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">9&#44;27&#8211;30</span></a> Likewise&#44; the combination <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;</span> was more frequently seen in AD patients than in controls &#40;OR&#58; 2&#46;06&#59; <span class="elsevierStyleItalic">P</span>corr<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;036&#41;&#46; These results suggest that the null genotype <span class="elsevierStyleItalic">GSTM1</span> and the combination <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;</span> could confer up to twice the risk of developing AD&#46; Considering that a variety of studies suggest that variations in the <span class="elsevierStyleItalic">APOE</span> gene may be genetic risk factors for AD&#44;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">31&#8211;33</span></a> we recorded the combinations of <span class="elsevierStyleItalic">GSTT1&#47;GSTM1</span> and <span class="elsevierStyleItalic">APOE</span> genotypes and obtained interesting results&#46; The genotype combinations <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;&#47;¿3¿4</span> and <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;&#47;¿4¿4</span> were significantly more frequent in patients than in controls&#46; These combinations may therefore be linked to increased likelihood of developing AD&#46; Additionally&#44; the risk posed by the presence of one or 2 <span class="elsevierStyleItalic">¿4</span> alleles of the <span class="elsevierStyleItalic">APOE</span> gene is higher in the combination in which the <span class="elsevierStyleItalic">GSTM1</span> gene is absent&#46; Considering the above&#44; an increase in A&#946; peptide aggregation due to the E4 isoform of apolipoprotein E&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">34</span></a> together with the reduction in antioxidant defences caused by homozygotic elimination of the <span class="elsevierStyleItalic">GSTM1</span> gene&#44; could generate greater oxidative stress&#46; This in turn would give rise to more neuronal death and explain how the risk inherent to allele ¿4 of the <span class="elsevierStyleItalic">APOE</span> gene would multiply in the absence of the <span class="elsevierStyleItalic">GSTM1</span> gene&#46; Furthermore&#44; combinations including wild-type <span class="elsevierStyleItalic">GSTT1</span> and <span class="elsevierStyleItalic">GSTM1</span> and at least one <span class="elsevierStyleItalic">¿3</span> allele &#91;<span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#43;&#47;¿2¿3</span> and <span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#43;&#47;¿3¿3</span>&#93; were significantly more frequent in healthy controls than in AD patients&#46; This suggests that these combinations may provide protection against the onset of AD&#46; A&#946; peptides are components of the senile plaques that begin degeneration of brain neurons in AD by increasing the presence of ROS until it exceeds the defence ability of each cell&#46; Kaminsky and Kosenko<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">35</span></a> studied the effects of A&#946; peptides on antioxidant enzymes from mitochondrial and non-mitochondrial sources in the rat brain in vivo&#46; They observed that A&#946; peptides increase the enzymatic activities creating H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> while inhibiting the activity of enzymes that consume H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> in the mitochondria and cytosol&#46; This finding suggests that the imbalance between enzymes generating and those metabolising H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> contribute to the underlying oxidative stress in the neurodegeneration and neuronal death that occur in AD&#46; Furthermore&#44; the A&#946; peptide has been found to be involved in the decreased expression of cytochrome c oxidase in the mitochondria&#44; which in turn affects the electron transport chain and produces ROS&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">3</span></a> The MnSOD enzyme forms part of the cell&#39;s enzymatic antioxidant defences&#44; and in fact provides the cell&#39;s first line of defence against the superoxide anion by converting it into H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">12</span></a> Multiple studies now support that MnSOD plays a role in how neurons survive oxidative stress&#46; One such study&#44; performed in <span class="elsevierStyleItalic">MnSOD</span> gene-knockout mice&#44; reported that the mice died not long after birth with signs of neurodegeneration&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">15&#44;16</span></a> Similarly&#44; studies in transgenic rats have reported that MnSOD deficiency increases the concentrations of the A&#946; peptide&#44; which favours the formation of senile plaques&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">36</span></a> However&#44; other studies have reported that overexpression of the MnSOD enzyme actually protects neurons from oxidative damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">37&#8211;39</span></a> In light of this conflicting evidence&#44; we studied the <span class="elsevierStyleItalic">Ala-9Val</span> polymorphism of the <span class="elsevierStyleItalic">MnSOD</span> gene that alters the secondary structure of that protein&#44; and therefore the mitochondrial transport of MnSOD&#46; This affects the cell&#39;s ability to defend itself from superoxide radicals&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">40</span></a> A comparison of the frequencies of the <span class="elsevierStyleItalic">Ala-9Val</span> genotypes of <span class="elsevierStyleItalic">MnSOD</span> showed that genotype <span class="elsevierStyleItalic">Ala&#47;Ala</span> was significantly more frequent in patients than in healthy controls&#46; This finding does not coincide with the results from an Italian population reported by Ventriglia et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">13</span></a> Furthermore&#44; evaluating the combined effect of the <span class="elsevierStyleItalic">MnSOD</span> and <span class="elsevierStyleItalic">APOE</span> genes revealed that the frequencies of the combinations <span class="elsevierStyleItalic">AlaAla&#47;¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;4&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;03&#41; and <span class="elsevierStyleItalic">AlaVal&#47;¿4¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;9&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41; were significantly higher in patients than in controls&#44; meaning that these combinations may indicate a greater susceptibility to AD&#46; The presence of the <span class="elsevierStyleItalic">Ala</span> allele&#44; which is associated with greater enzymatic activity of MnSOD in humans&#44; as well as the presence of allele ¿<span class="elsevierStyleItalic">4</span>&#44; promotes the development of AD&#46; We should point out that the risk associated with genotypes ¿<span class="elsevierStyleItalic">3</span>¿<span class="elsevierStyleItalic">4</span> and ¿<span class="elsevierStyleItalic">4</span>¿<span class="elsevierStyleItalic">4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;93 and OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;29&#44; respectively&#41; is approximately twice as high when the genotypes <span class="elsevierStyleItalic">AlaAla</span> and <span class="elsevierStyleItalic">AlaVal</span> of the <span class="elsevierStyleItalic">MnSOD</span> gene are present &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;4 and OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;9&#44; respectively&#41;&#46; In contrast&#44; the genotypic combinations <span class="elsevierStyleItalic">AlaVal&#47;¿2¿3</span>&#44; <span class="elsevierStyleItalic">AlaVal&#47;¿3¿3</span>&#44; and <span class="elsevierStyleItalic">ValVal&#47;¿2¿3</span> were only present in healthy individuals&#46; This suggests that they may play a protective role against AD&#46; Allele ¿<span class="elsevierStyleItalic">3</span>&#44; whether present homozygously or with allele ¿<span class="elsevierStyleItalic">2</span>&#44; together with one or 2 doses of the <span class="elsevierStyleItalic">Val</span> allele that is associated with abnormal enzymatic activity by MnSOD&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">40&#44;41</span></a> would therefore protect individuals from developing AD&#46; Considering that the <span class="elsevierStyleItalic">Ala</span> form of MnSOD is more efficiently transported to the mitochondria than the <span class="elsevierStyleItalic">Val</span> form&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">14</span></a> and that this enzyme catalyses the dismutation of the superoxide anion in H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> so that it can subsequently be removed from the mitochondria by the action of catalase and glutathione peroxidase&#44; researchers have suggested that the increased enzymatic activity of MnSOD would result in more production of H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span>&#46; This in turn would create an imbalance between H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> generation and metabolism that would promote oxidative stress and damage within the cell&#46; Such an imbalance might be due to reduced activity of the enzymes contributing to H<span class="elsevierStyleInf">2</span>O<span class="elsevierStyleInf">2</span> elimination&#44; such as catalase and glutathione peroxidase&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">35&#44;42</span></a> The results support the hypothesis that deterioration of the mitochondrial function and increased oxidative damage are involved in AD pathogenesis&#46; It is important&#44; nonetheless&#44; to point out that other genes linked to oxidative stress and antioxidant pathways may also affect susceptibility to developing AD&#44; and that their genetic variability should therefore be studied&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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              "titulo" => "Introduction"
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              "titulo" => "Introducci&#243;n"
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            1 => array:2 [
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              "titulo" => "M&#233;todos"
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          "titulo" => "Introduction"
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        5 => array:3 [
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          "titulo" => "Materials and methods"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Patients"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Genomic DNA extraction"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Detection of GSTT1&#47;GSTM1 genes"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Genotyping of the MnSOD gene"
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            4 => array:2 [
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              "titulo" => "Genotyping of the APOE gene"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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              "identificador" => "sec0050"
              "titulo" => "Genotype distribution and genotypic combination of GSTT1 and GSTM1 genes in healthy individuals and patients with Alzheimer disease"
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            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Allelic and genotypic frequencies of the MnSOD gene in healthy individuals and patients with Alzheimer disease"
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            2 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Allelic and genotypic frequency distributions of the MnSOD gene in healthy individuals and patients with Alzheimer disease"
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            3 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Study of the combined effect of polymorphism in GSTT1&#44; GSTM1 and APOE genes"
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            4 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Study of the combined effect of the polymorphism Ala-9Val in the genes MnSOD and APOE"
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          "titulo" => "Discussion"
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    "fechaAceptado" => "2014-10-10"
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            1 => "Alzheimer disease"
            2 => "<span class="elsevierStyleItalic">GSTM1</span>"
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            4 => "<span class="elsevierStyleItalic">MnSOD</span>"
            5 => "Oxidative damage"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Several studies have reported increased oxidation of lipids&#44; proteins and DNA in the brains of patients with Alzheimer disease &#40;AD&#41;&#46; Moreover&#44; these patients display differences in the activity and polymorphisms of the genes encoding the enzymes GST &#40;T1&#44; M1&#41; and MnSOD&#46; For these reasons&#44; we designed a study of the variability in <span class="elsevierStyleItalic">GSTT1</span>&#44; <span class="elsevierStyleItalic">GSTM1</span>&#44; and <span class="elsevierStyleItalic">MnSOD</span> genes in healthy and AD groups from a Venezuelan population&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We included 179 unrelated Venezuelan subjects classified as either AD patients &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>79&#41; or healthy individuals &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#41;&#46; Presence or absence of the <span class="elsevierStyleItalic">GSTT1</span>&#47;<span class="elsevierStyleItalic">GSTM1</span> genes was determined using PCR-SSP&#44; and polymorphisms of <span class="elsevierStyleItalic">MnSOD</span> and <span class="elsevierStyleItalic">APOE</span> genes were identified with PCR-RFLP&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The genotype <span class="elsevierStyleItalic">GSTT1</span>&#43;&#47;<span class="elsevierStyleItalic">GSTM1</span>&#8722; seems to favour development of AD &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;06&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46; The risk level is higher when it is combined with the ¿4 allele of the <span class="elsevierStyleItalic">APOE</span> gene&#58; <span class="elsevierStyleItalic">GSTT1</span>&#43;&#47;<span class="elsevierStyleItalic">GSTM1</span>&#8722;&#47;<span class="elsevierStyleItalic">¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;07&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#44; <span class="elsevierStyleItalic">GSTT1</span>&#43;&#47;<span class="elsevierStyleItalic">GSTM1</span>&#8722;&#47;<span class="elsevierStyleItalic">¿4¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;52&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#46; The <span class="elsevierStyleItalic">Ala-9Val</span> polymorphism does not appear to be related to AD&#46; However&#44; the presence of the Ala&#47;Ala genotype increases the risk provided by the ¿4 allele of the <span class="elsevierStyleItalic">APOE</span> gene&#58; <span class="elsevierStyleItalic">AlaAla&#47;¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;47&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;03&#41;&#44; <span class="elsevierStyleItalic">AlaAla&#47;¿4¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;3&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The results support the hypothesis that impaired mitochondrial function and increased oxidative damage are involved in the pathogenesis of AD&#46; It is important to study other genes related to oxidative stress and antioxidant pathways which could be involved in susceptibility to AD&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Diversos estudios han descrito que en los cerebros de pacientes con enfermedad de Alzheimer &#40;EA&#41; hay una mayor oxidaci&#243;n de l&#237;pidos&#44; prote&#237;nas y ADN&#46; Adem&#225;s&#44; en estos pacientes se ha observado diferencias en la actividad y polimorfismos de los genes que codifican las enzimas GST &#40;T1 y M1&#41; y MnSOD&#46; En virtud de ello se plante&#243; estudiar la variabilidad de los genes <span class="elsevierStyleItalic">GSTT1</span>&#44; <span class="elsevierStyleItalic">GSTM1</span> y <span class="elsevierStyleItalic">MnSOD</span> en individuos venezolanos sanos y con EA&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 179 individuos venezolanos&#44; no relacionados&#44; agrupados en pacientes con EA &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>79&#41; e individuos sanos &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#41;&#46; La presencia o ausencia de los genes <span class="elsevierStyleItalic">GSTT1</span>&#47;<span class="elsevierStyleItalic">GSTM1</span> se determin&#243; por PCR-SSP y los polimorfismo de los genes <span class="elsevierStyleItalic">MnSOD</span> y <span class="elsevierStyleItalic">APOE</span> por PCR-RFLP&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El genotipo <span class="elsevierStyleItalic">GSTT1</span>&#43;&#47;<span class="elsevierStyleItalic">GSTM1</span>&#8722; parece favorecer el desarrollo de la EA &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;06&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41;&#44; siendo el riesgo mayor al estar en combinaci&#243;n con el alelo ¿4 del gen <span class="elsevierStyleItalic">APOE</span>&#58; <span class="elsevierStyleItalic">GSTT1</span>&#43;&#47;<span class="elsevierStyleItalic">GSTM1</span>&#8722;&#47;<span class="elsevierStyleItalic">¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44;07&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#44; <span class="elsevierStyleItalic">GSTT1</span>&#43;&#47;<span class="elsevierStyleItalic">GSTM1</span>&#8722;&#47;<span class="elsevierStyleItalic">¿4¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#44;52&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;02&#41;&#46; El polimorfismo <span class="elsevierStyleItalic">Ala-9Val</span> por s&#237; solo no parece estar relacionado con la EA&#44; sin embargo&#44; la presencia del genotipo <span class="elsevierStyleItalic">Ala&#47;Ala</span> incrementa el riesgo que proporciona el alelo <span class="elsevierStyleItalic">¿4</span> del gen <span class="elsevierStyleItalic">APOE</span>&#58; <span class="elsevierStyleItalic">AlaAla&#47;¿3¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44;47&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#41;&#44; <span class="elsevierStyleItalic">AlaAla&#47;¿4¿4</span> &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#44;3&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los resultados apoyan la hip&#243;tesis de que el deterioro de la funci&#243;n mitocondrial y el aumento de da&#241;o oxidativo est&#225;n involucrados en la patog&#233;nesis de la EA&#46; Es importante estudiar otros genes relacionados con estr&#233;s oxidativo y v&#237;as antioxidantes&#44; los cuales pudiesen estar involucrados en la susceptibilidad a desarrollar la EA&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; de Mendon&#231;a E&#44; Salazar Alcal&#225; E&#44; Fern&#225;ndez-Mestre M&#46; Papel de las variantes <span class="elsevierStyleItalic">GSTM1</span>&#44; <span class="elsevierStyleItalic">GSTT1</span> y <span class="elsevierStyleItalic">MnSOD</span> en el desarrollo de enfermedad de Alzheimer de aparici&#243;n tard&#237;a y su relaci&#243;n con el alelo 4 de <span class="elsevierStyleItalic">APOE</span>&#46; Neurolog&#237;a&#46; 2016&#59;31&#58;535&#8211;542&#46;</p>"
      ]
    ]
    "multimedia" => array:5 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">AD&#58; Alzheimer disease&#59; 95&#37; CI&#58; confidence interval&#59; ns&#58; not significant&#59; OR&#58; odds ratio&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Values shown in parentheses indicate the number of individuals bearing the genotype for the polymorphic site under study&#46; Frequencies are expressed as percentages&#46;</p><p id="spar1045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">&#42;</span> Significant after applying the Bonferroni correction&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR<br>95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">GSTT1 alleles</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Wild-type &#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&#46;5 &#40;66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78 &#40;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Null &#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&#46;5 &#40;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22 &#40;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">GSTM1 alleles</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Wild-type &#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46&#46;8 &#40;37&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60 &#40;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Null &#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;2 &#40;42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Allele combinations</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GSTT1&#43; GSTM1&#8722;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35&#46;4 &#40;28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47 &#40;47&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GSTT1&#8722; GSTM1&#8722;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;1 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GSTT1&#43; GSTM1&#8722;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#46;1 &#40;38&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31 &#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;009<span class="elsevierStyleSup">&#42;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GSTT1&#8722; GSTM1&#43;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;4 &#40;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13 &#40;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Distribution of genotypes and genotype combinations for the genes <span class="elsevierStyleItalic">GSTT1</span> and <span class="elsevierStyleItalic">GSTM1</span> in patients with AD and healthy controls&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">AD&#58; Alzheimer disease&#59; 95&#37; CI&#58; confidence interval&#59; ns&#58; not significant&#59; OR&#58; odds ratio&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Values shown in parentheses indicate the number of repeats of the allele or the number of individuals bearing the genotype for the polymorphic site under study&#46; Frequencies are expressed as percentages&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Healthy<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR<br>95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Genotypes</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Ala&#47;Ala</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;6 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Ala&#47;Val</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&#46;4 &#40;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63 &#40;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Val&#47;Val</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Alleles</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Ala</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;8 &#40;85&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;5 &#40;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Val</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">46&#46;2 &#40;73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;5 &#40;105&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1213263.png"
              ]
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Allelic and genotypic frequency of the <span class="elsevierStyleItalic">Ala-9Val</span> polymorphism of the <span class="elsevierStyleItalic">MnSOD</span> gene in patients and controls&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">AD&#58; Alzheimer disease&#59; 95&#37; CI&#58; confidence interval&#59; ns&#58; not significant&#59; OR&#58; odds ratio&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Values in parentheses indicate the number of individuals bearing the genotype&#46; Frequencies are expressed as percentages&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR<br>95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Genotype</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>2&#47;<span class="elsevierStyleItalic">¿</span>3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;0007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>2&#47;<span class="elsevierStyleItalic">¿</span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;3 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>3&#47;<span class="elsevierStyleItalic">¿</span>3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">45&#46;6 &#40;36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60 &#40;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>3&#47;<span class="elsevierStyleItalic">¿</span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37&#46;9 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24 &#40;24&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>4&#47;<span class="elsevierStyleItalic">¿</span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;2 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Alleles</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;00002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64&#46;6 &#40;102&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78 &#40;156&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;513&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;0024&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">¿</span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">34&#46;8 &#40;55&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16 &#40;32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;000019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1213265.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Frequencies of genotypes and alleles of the <span class="elsevierStyleItalic">APOE</span> gene in patients with AD and controls&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">AD&#58; Alzheimer disease&#59; 95&#37; CI&#58; confidence interval&#59; OR&#58; odds ratio&#59; <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span>&#58; chi-square test&#46;</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Values in parentheses indicate the number of individuals bearing the genotype&#46; Frequencies are expressed as percentages&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AD<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR<br>95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span> &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Genotype</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#43;&#47;¿2¿3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#43;&#47;¿3¿3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14 &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26 &#40;26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GSTT1&#43;&#47;GSTM1&#8722;&#47;¿3¿4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14 &#40;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;07&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 21735808
Original language: English

DOI:10.1016/j.nrleng.2014.10.007

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Year/Month	Html	Pdf	Total

2024 November	5	0	5
2024 October	17	7	24
2024 September	40	7	47
2024 August	30	5	35
2024 July	16	6	22
2024 June	40	1	41
2024 May	31	2	33
2024 April	39	23	62
2024 March	127	12	139
2024 February	52	4	56
2024 January	52	6	58
2023 December	45	6	51
2023 November	39	5	44
2023 October	59	22	81
2023 September	36	5	41
2023 August	45	9	54
2023 July	27	5	32
2023 June	49	5	54
2023 May	57	10	67
2023 April	62	4	66
2023 March	83	6	89
2023 February	33	2	35
2023 January	36	5	41
2022 December	21	6	27
2022 November	20	6	26
2022 October	18	10	28
2022 September	19	14	33
2022 August	24	14	38
2022 July	32	11	43
2022 June	14	10	24
2022 May	16	9	25
2022 April	19	7	26
2022 March	16	11	27
2022 February	9	9	18
2022 January	21	7	28
2021 December	16	16	32
2021 November	16	5	21
2021 October	9	8	17
2021 September	13	14	27
2021 August	8	6	14
2021 July	42	8	50
2021 June	18	8	26
2021 May	17	11	28
2021 April	89	4	93
2021 March	17	12	29
2021 February	13	5	18
2021 January	8	11	19
2020 December	12	9	21
2020 November	15	9	24
2020 October	8	6	14
2020 September	9	8	17
2020 August	14	7	21
2020 July	6	7	13
2020 June	11	11	22
2020 May	7	17	24
2020 April	5	10	15
2020 March	17	6	23
2020 February	14	6	20
2020 January	11	3	14
2019 December	18	7	25
2019 November	12	9	21
2019 October	25	4	29
2019 September	18	3	21
2019 August	10	2	12
2019 July	12	11	23
2019 June	42	23	65
2019 May	107	6	113
2019 April	36	2	38
2019 March	23	5	28
2019 February	14	7	21
2019 January	5	8	13
2018 December	13	2	15
2018 November	15	12	27
2018 October	19	2	21
2018 September	9	2	11
2018 August	17	0	17
2018 July	3	4	7
2018 June	0	0	0
2018 May	6	2	8
2018 April	4	1	5
2018 March	4	1	5
2018 February	3	0	3
2018 January	1	0	1
2017 December	11	3	14
2017 November	8	1	9
2017 October	10	4	14
2017 September	11	4	15
2017 August	21	8	29
2017 July	14	1	15
2017 June	7	2	9
2017 May	6	3	9
2017 April	8	7	15
2017 March	15	53	68
2017 February	13	3	16
2017 January	12	6	18
2016 December	20	6	26
2016 November	36	9	45
2016 October	49	13	62
2016 September	13	1	14

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