Single-nucleotide polymorphisms of GSK3B, GAB2 and SORL1 in late-onset Alzheimer's disease: interactions with the APOE genotype

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Forlenza, Bernardo dos Santos, Paulo H.F. Bertolucci, Elida B. Ojopi, Wagner F. Gattaz, Daniel Shikanai Kerr" "autores" => array:7 [ 0 => array:3 [ "nombre" => "Giselle" "apellidos" => "Izzo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 1 => array:3 [ "nombre" => "Orestes V." "apellidos" => "Forlenza" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "IV" "identificador" => "aff4" ] ] ] 2 => array:3 [ "nombre" => "Bernardo" "apellidos" => "dos Santos" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "III" "identificador" => "aff3" ] ] ] 3 => array:3 [ "nombre" => "Paulo H.F." "apellidos" => "Bertolucci" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "II" "identificador" => "aff2" ] ] ] 4 => array:3 [ "nombre" => "Elida B." "apellidos" => "Ojopi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] ] ] 5 => array:3 [ "nombre" => "Wagner F." "apellidos" => "Gattaz" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "IV" "identificador" => "aff4" ] ] ] 6 => array:4 [ "nombre" => "Daniel Shikanai" "apellidos" => "Kerr" "email" => array:1 [ 0 => "dskerr@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "IV" "identificador" => "aff4" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Faculdade de Medicina da Universidade de São Paulo (Ipq-FMUSP), Department and Institute of Psychiatry), Laboratory of Neuroscience (LIM-27), São Paulo/SP, Brazil." "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Federal University of São Paulo (UNIFESP), Faculty of Medicine, Department of Neurology, Núcleo De Envelhecimento Cerebral (NUDEC), São Paulo/SP, Brazil." "etiqueta" => "II" "identificador" => "aff2" ] 2 => array:3 [ "entidad" => "Universidade de São Paulo, Instituto de Matemática e Estatística (IME), São Paulo/SP, Brazil." "etiqueta" => "III" "identificador" => "aff3" ] 3 => array:3 [ "entidad" => "Universidade São Paulo, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), São Paulo/SP, Brazil." "etiqueta" => "IV" "identificador" => "aff4" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Tel.: 55-11-2661-7283" ] ] ] ] "textoCompleto" => "INTRODUCTIONAlzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that is caused by the interaction of multiple genetic and environmental factors (<a class="elsevierStyleCrossRef" href="#bib1">1</a>). In the early stages, Alzheimer’s disease is clinically characterized by short-term memory impairment, which evolves to widespread cognitive decline and dementia. There is unequivocal evidence that genetic factors contribute to the pathogenesis of Alzheimer’s disease, including the sporadic form (<a class="elsevierStyleCrossRef" href="#bib2">2</a>). Currently, apolipoprotein E is the only well-established genetic risk factor for sporadic Alzheimer’s disease, and the APOE∗4 allele has been consistently shown to be associated with an increased risk of Alzheimer’s disease (<a class="elsevierStyleCrossRefs" href="#bib3">3,4</a>). There is little doubt that other – most likely multiple – polymorphisms play an important role in the pathophysiology of Alzheimer’s disease, given that the presence of one or even two copies of APOE∗4 is neither a necessary nor sufficient condition for developing the disease.Several new single-nucleotide polymorphisms (SNPs) associated with on Alzheimer’s disease have recently been identified in genome-wide association studies, namely PICALM, CLU, CR1 and SORL1 (<a class="elsevierStyleCrossRefs" href="#bib5">5-7</a>). None of these SNPs can be regarded as etiological factors; rather, they serve as susceptibility modifiers, i.e., factors with independent or additive effects in the interactions among several genetic variants (mostly SNPs) at multiple genomic loci. These variants may not be deleterious per se, but they may modify disease outcomes as a result of direct and indirect interactions with other genetic and environmental factors (<a class="elsevierStyleCrossRefs" href="#bib8">8,9</a>).Polymorphisms in the SORL1, GAB2 and GSK3B genes have been shown to be associated with Alzheimer’s disease in recent studies. Association studies have yielded conflicting data regarding the role of SORL1 rs641120 in Alzheimer’s disease (<a class="elsevierStyleCrossRefs" href="#bib7">7,10,11-13</a>). A recent study showed that there were age-dependent differences in SORL1 expression and promoter methylation in an AD cohort, with possible implications for the disease (<a class="elsevierStyleCrossRef" href="#bib14">14</a>). Likewise, two studies suggested that there is an association between GAB2 polymorphisms and AD in Caucasians (<a class="elsevierStyleCrossRefs" href="#bib15">15,16</a>), but other studies failed to confirm this association in European (<a class="elsevierStyleCrossRef" href="#bib17">17</a>) and Asiatic populations (<a class="elsevierStyleCrossRefs" href="#bib12">18,19</a>). Only one study to date has addressed the association between GSK3B polymorphisms and AD; the results of that study suggest that rs6438552 has a significant effect on disease risk (<a class="elsevierStyleCrossRef" href="#bib20">20</a>). Therefore, the objective of the present study was to determine the effects of GAB2 (rs2373115), GSK3B (rs6438552) and SORL1 (rs641120) polymorphisms on the risk for AD and to investigate the interactions of these SNPs with APOE∗4 in a sample of 201 older Brazilian adults.MATERIALS AND METHODSSubjects were recruited from two university-based memory clinics in Sao Paulo, Brazil. All participants underwent comprehensive clinical and neuropsychological evaluations. The diagnosis of probable AD (n = 130, mean age 77±8.3, 66% females) was established according to the NINCDS-ADRDA criteria (<a class="elsevierStyleCrossRef" href="#bib21">21</a>). The comparison group included healthy volunteers (n = 71, mean age 71.8±6.7; 79% females) with no signs of cognitive or functional impairment. No relatives of AD patients were included in the control group. No statistically significant differences were observed with respect to the age distribution or self-reported ethnic background between the patients and controls, but there was a greater percentage of females in the control group. However, we believe that this gender difference should not negatively affect the findings, as similar results were obtained in a preliminary analysis of gender-matched samples.The GSK3B, GAB2 and SORL1 SNPs were analyzed using a Real-Time PCR SNP genotyping system (TaqMan® Assays – Applied Biosystems, CA, USA) TaqMan PCR Master Mix 1x, TaqMan SNP genotyping assay 1x, genomic DNA 10 ng/μL and ultrapure water to a volume of 5 μL were mixed in each well of an optical plate. Allelic discrimination was performed using a 7500 Real-Time PCR system (Applied Biosystems, CA, USA) by comparing the fluorescence levels before and after amplification (45 cycles of 15 seconds at 95 °C and 1 min at 60 °C). Two SNPs (rs7412 and rs429358) were evaluated to determine the APOE genotype, as previously described (<a class="elsevierStyleCrossRef" href="#bib22">22</a>). The real-time PCR reactions were run using the protocol presented above.Pearson's Chi-squared test with simulated p-values was used to compare the genotype distributions between cases and controls. The interactions between the GSK3B, GAB2 and SORL1 SNPs and APOE∗4 were tested in two ways: first, each group was stratified into APOE∗4-positive and APOE∗4-negative subgroups, and the association between each SNP and the diagnosis of AD was assessed separately in each group. In the second step, a binomial logistic regression model was used to compare the interactions between APOE∗4 and each of the three SNPs in the entire sample. The statistical analysis was conducted using R software version 2.12.2.RESULTS AND DISCUSSIONOur results are consistent with the well-established role of the APOE∗4 allele as a risk factor for sporadic AD (p<0.0001) (<a class="elsevierStyleCrossRef" href="#bib3">3</a>, <a class="elsevierStyleCrossRef" href="#bib5">5</a>, <a class="elsevierStyleCrossRef" href="#bib6">6</a>, <a class="elsevierStyleCrossRefs" href="#bib23">23-25</a>)(7). Data regarding the genetics of AD in the Brazilian population remain scarce (<a class="elsevierStyleCrossRef" href="#bib26">26</a>, <a class="elsevierStyleCrossRef" href="#bib27">27</a>), underscoring the importance of our findings. We call attention to the positive association of all the studied SNPs, namely GAB2 rs2373115, GSK3B rs6438552 and SORL1 rs641120, with AD (<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>). The association of the GG genotype of SORL1 with AD (p = 0.047, OR = 2.07, CI95% [1.17 - 3.68]) was independent of APOE, and the binomial logistic regression analysis showed no interaction effect between APOE∗4 and any of the SORL1 genotypes (<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>). We conclude that SORL1 has an independent role in AD, irrespective of the presence of the APOE∗4 allele.<elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl2"></elsevierMultimedia>We found a positive association between the GG genotype of GAB2 (rs2373115) and the diagnosis of AD (p = 0.021, OR = 1.8, CI95% [1.01-3.18]). This genotype was associated with a greater odds ratio (OR) for AD in the APOE∗4 carriers (p = 0.006, OR = 5.08, CI95% [1.45-18.98]). We further used logistic regression to investigate the interaction between the APOE∗4 and GAB2 polymorphisms (GG vs. non-GG genotypes, given the small proportion of individuals with the TT genotype in our sample), and we observed a robust increase in the effect as a result of the interaction between GAB2 GG and APOE∗4 (p = 0.014, ORinteraction = 7.95, ORmain = 1.44) (<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>).With respect to the association between the GSK3B polymorphism (rs6438552) and AD diagnosis, we found that the GG genotype was approximately twice as common in the AD group (28.8%) than in the controls (13.8%) and that this genotype had a significant effect on the OR (p = 0.018, OR = 2.48, CI95% [1.19-5.20]). Interestingly, this effect was even more pronounced in the absence of APOE∗4 (p = 0.003, OR = 4.45, CI95% [1.47-16.39]). In contrast, the A allele was associated with a protective effect, irrespective of the APOE status (p = 0.018, OR = 0.40, CI95% [0.19-0.84]); however, the logistic regression analysis showed that APOE∗4-positive carriers of the AA genotype displayed an increased OR for AD (p = 0.024, ORinteraction = 1.10, ORmain = 0.19) (<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>). This finding is noteworthy because it indicates that the A allele of the GSK3B gene may represent either a protective factor or a risk factor for AD, depending on the APOE genotype. We speculate that this dual role may occur because the rs6438552 polymorphism is intronic and may affect the transcription and splicing of GSK3B. In fact, splice variants of GSK3B arising from the AA genotype have been shown to favor Tau protein hyperphosphorylation, which is one of the pathological hallmarks of AD (<a class="elsevierStyleCrossRef" href="#bib28">28</a>).APOE∗4 is involved in the abnormal cleavage of the amyloid-precursor protein (APP), leading to the accumulation of the amyloid-beta peptide, which in turn favors the hyperphosphorylation of Tau. These pathological changes ultimately disrupt axonal transport and neuronal viability (<a class="elsevierStyleCrossRef" href="#bib29">29</a>, <a class="elsevierStyleCrossRef" href="#bib30">30</a>). GAB2 and GSK3B (rs6438552, AA genotype) have been shown to increase Tau phosphorylation (<a class="elsevierStyleCrossRef" href="#bib15">15</a>, <a class="elsevierStyleCrossRef" href="#bib28">28</a>). The studied GSK3B and GAB2 polymorphisms are located in intronic regions of these genes and may thus have subtle effects on transcription, with biological consequences that are yet to be defined. It is also possible that these SNPs are in linkage disequilibrium with other polymorphisms that may contribute to the observed effects. GAB2 is a scaffolding protein with important roles in several growth and differentiation signaling pathways, including the phosphorylation of kinases that participate in core neurobiological pathways related to AD (<a class="elsevierStyleCrossRefs" href="#bib15">15,16,31,32</a>). GAB2 and presenilin 1 both activate PI3K, leading to the activation of PKB and the further inactivation of GSK3B (<a class="elsevierStyleCrossRef" href="#bib33">33</a>). Because the inactivation of GSK3B prevents Tau hyperphosphorylation in neurons (<a class="elsevierStyleCrossRef" href="#bib34">34</a>), it is reasonable to assume that any decrease in GAB2 expression and/or function would increase Tau phosphorylation (<a class="elsevierStyleCrossRef" href="#bib15">15</a>). Supporting this hypothesis, in vitro studies have shown that the inhibition of GAB2 expression using siRNA increases Tau phosphorylation (<a class="elsevierStyleCrossRef" href="#bib15">15</a>).We conclude that interactions between the GAB2 and GSK3B polymorphisms and the well-established genetic factor APOE may modify the overall risk of AD. These effects are by no means linear or cumulative, given that the protective effect of a one studied polymorphism (e.g., the AA genotype of GSK3B) may increase the odds ratio for AD in the presence of APOE∗4. Our results support the hypothesis that there is no single genetic cause for late-onset AD; instead, the development of AD depends on the interaction of several genes, environmental factors and age. Further evaluation of the interactions between distinct genes and of the respective implications on neuronal homeostasis may provide insight into the complex neurobiology of AD." "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" ] 1 => array:2 [ "identificador" => "cesec20" "titulo" => "MATERIALS AND METHODS" ] 2 => array:2 [ "identificador" => "cesec30" "titulo" => "RESULTS AND DISCUSSION" ] 3 => array:2 [ "identificador" => "xack639462" "titulo" => "ACKNOWLEDGMENTS" ] 4 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => "In this study, we investigated the associations between single-nucleotide polymorphisms in GAB2 (rs2373115), GSK3B (rs6438552) and SORL1 (rs641120) and Alzheimer’s disease (AD), both alone and in combination with the APOE∗4 allele." ] ] "NotaPie" => array:1 [ 0 => array:1 [ "nota" => "No potential conflict of interest was reported. All authors contributed to the present work and consent to the publication of the findings. Gattaz WF and Ojopi EB were responsible for the initial concept. The patients were recruited by Bertolucci PHF, Forlenza OV and Gattaz WF. The experimental analyses were performed by Izzo G and Kerr DS. The statistical analyses were performed by Santos B and Kerr DS. Izzo G wrote the first draft of the manuscript. The literature review was performed by by Izzo G and Kerr DS. The manuscript was prepared and formatted and the tables were prepared by Kerr DS and Forlenza OV. All authors have reviewed and approved the final manuscript." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "The OR for APOE was calculated by comparing APOE∗4 carriers with non-carriers. The ORs for other genes compared the homozygous risk allele genotype with the remaining cohort (e.g., GG vs. GT + TT)." "tablatextoimagen" => array:1 [ 0 => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">DbSNP rs ID \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Risk Allele \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Freq. Cases \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Freq. Controls \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">p-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">429358 7412 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.33 (1.73-6.63) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GAB2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2373115 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.79 (1.01-3.18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.021 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE∗4+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.08 (1.45-18.98) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.006 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE∗4- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.10 (0.51-2.35) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.859 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GSK3B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6438552 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.48 (1.19-5.20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.018 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE∗4+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.76 (0.22-2.88) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.768 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE∗4- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.45 (1.47-16.39) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SORL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">641120 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.07 (1.17-3.68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.047 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE∗4+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.02 (0.58-7.31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.260 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">APOE∗4- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">2.01 (0.94-4.34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">0.054 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Polymorphisms associated with Alzheimer's disease and sample stratification based on the presence or absence of the APOE∗4 allele." ] ] 1 => array:7 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">DbSNP rs ID \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Interaction \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">OR interaction \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">OR main effects \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">p-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GAB2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2373115 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>)4:GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.014<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>)4:TT ‡ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GSK3B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64384552 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>)4:GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.211 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>)4:AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.024<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SORL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">641120 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APOE<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>)4:GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.140 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">APOE<a class="elsevierStyleCrossRef" href="#tfn2">∗</a>)4:AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">5.39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">31.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">0.989 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tfn2" "etiqueta" => "∗" "nota" => "p<0.05. The OR interaction values were obtained by logistic regression evaluating the interaction between APOE∗4 and the given genotype. ‡ Because there were very few individuals who were homozygous for the T allele, this interaction was discarded." ] ] ] "descripcion" => array:1 [ "en" => "Logistic regression analysis of the risk genotype for LOAD in APOE∗4 individuals." ] ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The genetics of adult-onset neuropsychiatric disease: complexities and conundra?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ JL Kennedy \n \t\t\t\t\t\t\t\t """ 1 => """ LA Farrer \n \t\t\t\t\t\t\t\t """ 2 => """ NC Andreasen \n \t\t\t\t\t\t\t\t """ 3 => """ R Mayeux \n \t\t\t\t\t\t\t\t """ 4 => """ P St George-Hyslop \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Science" "fecha" => "2003" "volumen" => "302" "numero" => "5646" "paginaInicial" => "6" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of genes and environments for explaining Alzheimer disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Gatz \n \t\t\t\t\t\t\t\t """ 1 => """ CA Reynolds \n \t\t\t\t\t\t\t\t """ 2 => """ L Fratiglioni \n \t\t\t\t\t\t\t\t """ 3 => """ B Johansson \n \t\t\t\t\t\t\t\t """ 4 => """ JA Mortimer \n 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"host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Dement Geriatr Cogn Disord" "fecha" => "2007" "volumen" => "24" "numero" => "2" "paginaInicial" => "103" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Apolipoprotein E4 and Alzheimer's disease in Sao Paulo-Brazil" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ OP Almeida \n \t\t\t\t\t\t\t\t """ 1 => """ CM Shimokomaki \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arquivos de neuro-psiquiatria" "fecha" => "1997" "volumen" => "55" "numero" => "1" "paginaInicial" => "7" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ D Harold \n \t\t\t\t\t\t\t\t """ 1 => """ R Abraham \n \t\t\t\t\t\t\t\t """ 2 => """ P Hollingworth \n \t\t\t\t\t\t\t\t """ 3 => """ R Sims \n \t\t\t\t\t\t\t\t """ 4 => """ A Gerrish \n \t\t\t\t\t\t\t\t """ 5 => """ ML Hamshere \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Nat Genet" "fecha" => "2009" "volumen" => "41" "numero" => "10" "paginaInicial" => "93" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ J Lambert \n \t\t\t\t\t\t\t\t """ 1 => """ S Heath \n \t\t\t\t\t\t\t\t """ 2 => """ G Even \n \t\t\t\t\t\t\t\t """ 3 => """ D Campion \n \t\t\t\t\t\t\t\t """ 4 => """ K Sleegers \n \t\t\t\t\t\t\t\t """ 5 => """ M Hiltunen \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Nat Genet" "fecha" => "2009" "volumen" => "41" "numero" => "10" "paginaInicial" => "9" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between SORL1 and Alzheimer's disease in a genome-wide study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ Y Meng \n \t\t\t\t\t\t\t\t """ 1 => """ JH Lee \n \t\t\t\t\t\t\t\t """ 2 => """ R Cheng \n \t\t\t\t\t\t\t\t """ 3 => """ P St George-Hyslop \n \t\t\t\t\t\t\t\t """ 4 => """ R Mayeux \n \t\t\t\t\t\t\t\t """ 5 => """ LA Farrer \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Neuroreport" "fecha" => "2007" "volumen" => "18" "numero" => "17" "paginaInicial" => "4" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "From Darwin's finches to canaries in the coal mine–mining the genome for new biology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ DJ Hunter \n \t\t\t\t\t\t\t\t """ 1 => """ D Altshuler \n \t\t\t\t\t\t\t\t """ 2 => """ DJ Rader \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMp0804318" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "2008" "volumen" => "358" "numero" => "26" "paginaInicial" => "2760" "paginaFinal" => "2763" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18579810" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A glimmer of light for neuropsychiatric disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ SE Hyman \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Nature" "fecha" => "2008" "volumen" => "455" "numero" => "7215" "paginaInicial" => "3" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ K Bettens \n \t\t\t\t\t\t\t\t """ 1 => """ N Brouwers \n \t\t\t\t\t\t\t\t """ 2 => """ S Engelborghs \n \t\t\t\t\t\t\t\t """ 3 => """ PP De Deyn \n \t\t\t\t\t\t\t\t """ 4 => """ C Van Broeckhoven \n \t\t\t\t\t\t\t\t """ 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"autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ B Nawrot \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Acta Biochim Pol" "fecha" => "2004" "volumen" => "51" "numero" => "2" "paginaInicial" => "44" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments of APP via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ C Russo \n \t\t\t\t\t\t\t\t """ 1 => """ V Dolcini \n \t\t\t\t\t\t\t\t """ 2 => """ S Salis \n \t\t\t\t\t\t\t\t """ 3 => """ V Venezia \n \t\t\t\t\t\t\t\t """ 4 => """ E Violani \n \t\t\t\t\t\t\t\t """ 5 => """ P Carlo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Ann N Y Acad Sci" "fecha" => "2002" "volumen" => "973" "paginaInicial" => "33" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Amyloid precursor protein and Presenilin1 interact with the adaptor GRB2 and modulate ERK 1,2 signaling" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Nizzari \n \t\t\t\t\t\t\t\t """ 1 => """ V Venezia \n \t\t\t\t\t\t\t\t """ 2 => """ E Repetto \n \t\t\t\t\t\t\t\t """ 3 => """ V Caorsi \n \t\t\t\t\t\t\t\t """ 4 => """ R Magrassi \n \t\t\t\t\t\t\t\t """ 5 => """ MC Gagliani \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Biol Chem" "fecha" => "2007" "volumen" => "282" "numero" => "18" "paginaInicial" => "44" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ L Baki \n \t\t\t\t\t\t\t\t """ 1 => """ J Shioi \n \t\t\t\t\t\t\t\t """ 2 => """ P Wen \n \t\t\t\t\t\t\t\t """ 3 => """ Z Shao \n \t\t\t\t\t\t\t\t """ 4 => """ A Schwarzman \n \t\t\t\t\t\t\t\t """ 5 => """ M Gama-Sosa \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "EMBO J" "fecha" => "2004" "volumen" => "23" "numero" => "13" "paginaInicial" => "96" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "GSK3: a possible link between beta amyloid peptide and tau protein" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ F Hernández \n \t\t\t\t\t\t\t\t """ 1 => """ E Gómez de Barreda \n \t\t\t\t\t\t\t\t """ 2 => """ A Fuster-Matanzo \n \t\t\t\t\t\t\t\t """ 3 => """ JJ Lucas \n \t\t\t\t\t\t\t\t """ 4 => """ J Avila \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.expneurol.2009.08.010" "Revista" => array:6 [ "tituloSerie" => "Exp Neurol" "fecha" => "2010" "volumen" => "223" "numero" => "2" "paginaInicial" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19699198" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack639462" "titulo" => "ACKNOWLEDGMENTS" "texto" => "We would like to thank CNPq, CAPES, FAPESP and ABADHS for financial support." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/18075932/0000006800000002/v1_202212011614/S1807593222021147/v1_202212011614/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/18075932/0000006800000002/v1_202212011614/S1807593222021147/v1_202212011614/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222021147?idApp=UINPBA00004N"]

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Giselle IzzoI, Orestes V. ForlenzaI,IV, Bernardo dos SantosI,III, Paulo H.F. BertolucciII, Elida B. OjopiI, Wagner F. GattazI,IV, Daniel Shikanai KerrI,IV,

Corresponding author

dskerr@gmail.com

Tel.: 55-11-2661-7283

I Faculdade de Medicina da Universidade de São Paulo (Ipq-FMUSP), Department and Institute of Psychiatry), Laboratory of Neuroscience (LIM-27), São Paulo/SP, Brazil.

II Federal University of São Paulo (UNIFESP), Faculty of Medicine, Department of Neurology, Núcleo De Envelhecimento Cerebral (NUDEC), São Paulo/SP, Brazil.

III Universidade de São Paulo, Instituto de Matemática e Estatística (IME), São Paulo/SP, Brazil.

IV Universidade São Paulo, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), São Paulo/SP, Brazil.

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Alzheimer&#8217;s disease &#40;AD&#41; is a multifactorial neurodegenerative disorder that is caused by the interaction of multiple genetic and environmental factors &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; In the early stages&#44; Alzheimer&#8217;s disease is clinically characterized by short-term memory impairment&#44; which evolves to widespread cognitive decline and dementia&#46; There is unequivocal evidence that genetic factors contribute to the pathogenesis of Alzheimer&#8217;s disease&#44; including the sporadic form &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; Currently&#44; apolipoprotein E is the only well-established genetic risk factor for sporadic Alzheimer&#8217;s disease&#44; and the <span class="elsevierStyleItalic">APOE&#8727;4</span> allele has been consistently shown to be associated with an increased risk of Alzheimer&#8217;s disease &#40;<a class="elsevierStyleCrossRefs" href="#bib3">3&#44;4</a>&#41;&#46; There is little doubt that other &#8211; most likely multiple &#8211; polymorphisms play an important role in the pathophysiology of Alzheimer&#8217;s disease&#44; given that the presence of one or even two copies of <span class="elsevierStyleItalic">APOE&#8727;4</span> is neither a necessary nor sufficient condition for developing the disease&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Several new single-nucleotide polymorphisms &#40;SNPs&#41; associated with on Alzheimer&#8217;s disease have recently been identified in genome-wide association studies&#44; namely <span class="elsevierStyleItalic">PICALM</span>&#44; <span class="elsevierStyleItalic">CLU&#44; CR1</span> and <span class="elsevierStyleItalic">SORL1</span> &#40;<a class="elsevierStyleCrossRefs" href="#bib5">5-7</a>&#41;&#46; None of these SNPs can be regarded as etiological factors&#59; rather&#44; they serve as susceptibility modifiers&#44; i&#46;e&#46;&#44; factors with independent or additive effects in the interactions among several genetic variants &#40;mostly SNPs&#41; at multiple genomic loci&#46; These variants may not be deleterious per se&#44; but they may modify disease outcomes as a result of direct and indirect interactions with other genetic and environmental factors &#40;<a class="elsevierStyleCrossRefs" href="#bib8">8&#44;9</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Polymorphisms in the <span class="elsevierStyleItalic">SORL1</span>&#44; <span class="elsevierStyleItalic">GAB2</span> and <span class="elsevierStyleItalic">GSK3B</span> genes have been shown to be associated with Alzheimer&#8217;s disease in recent studies&#46; Association studies have yielded conflicting data regarding the role of <span class="elsevierStyleItalic">SORL1</span> rs641120 in Alzheimer&#8217;s disease &#40;<a class="elsevierStyleCrossRefs" href="#bib7">7&#44;10&#44;11-13</a>&#41;&#46; A recent study showed that there were age-dependent differences in <span class="elsevierStyleItalic">SORL1</span> expression and promoter methylation in an AD cohort&#44; with possible implications for the disease &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46; Likewise&#44; two studies suggested that there is an association between <span class="elsevierStyleItalic">GAB2</span> polymorphisms and AD in Caucasians &#40;<a class="elsevierStyleCrossRefs" href="#bib15">15&#44;16</a>&#41;&#44; but other studies failed to confirm this association in European &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41; and Asiatic populations &#40;<a class="elsevierStyleCrossRefs" href="#bib12">18&#44;19</a>&#41;&#46; Only one study to date has addressed the association between <span class="elsevierStyleItalic">GSK3B</span> polymorphisms and AD&#59; the results of that study suggest that rs6438552 has a significant effect on disease risk &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46; Therefore&#44; the objective of the present study was to determine the effects of <span class="elsevierStyleItalic">GAB2</span> &#40;rs2373115&#41;&#44; <span class="elsevierStyleItalic">GSK3B</span> &#40;rs6438552&#41; and <span class="elsevierStyleItalic">SORL1</span> &#40;rs641120&#41; polymorphisms on the risk for AD and to investigate the interactions of these SNPs with <span class="elsevierStyleItalic">APOE</span>&#8727;4 in a sample of 201 older Brazilian adults&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">MATERIALS AND METHODS</span><p id="para40" class="elsevierStylePara elsevierViewall">Subjects were recruited from two university-based memory clinics in Sao Paulo&#44; Brazil&#46; All participants underwent comprehensive clinical and neuropsychological evaluations&#46; The diagnosis of probable AD &#40;n&#8202;&#61;&#8202;130&#44; mean age 77&#177;8&#46;3&#44; 66&#37; females&#41; was established according to the NINCDS-ADRDA criteria &#40;<a class="elsevierStyleCrossRef" href="#bib21">21</a>&#41;&#46; The comparison group included healthy volunteers &#40;n&#8202;&#61;&#8202;71&#44; mean age 71&#46;8&#177;6&#46;7&#59; 79&#37; females&#41; with no signs of cognitive or functional impairment&#46; No relatives of AD patients were included in the control group&#46; No statistically significant differences were observed with respect to the age distribution or self-reported ethnic background between the patients and controls&#44; but there was a greater percentage of females in the control group&#46; However&#44; we believe that this gender difference should not negatively affect the findings&#44; as similar results were obtained in a preliminary analysis of gender-matched samples&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">GSK3B</span>&#44; <span class="elsevierStyleItalic">GAB2</span> and <span class="elsevierStyleItalic">SORL1</span> SNPs were analyzed using a Real-Time PCR SNP genotyping system &#40;<span class="elsevierStyleItalic">TaqMan&#174;</span> Assays &#8211; Applied Biosystems&#44; CA&#44; USA&#41; <span class="elsevierStyleItalic">TaqMan</span> PCR Master Mix 1x&#44; <span class="elsevierStyleItalic">TaqMan</span> SNP genotyping assay 1x&#44; genomic DNA 10 ng&#47;&#956;L and ultrapure water to a volume of 5 &#956;L were mixed in each well of an optical plate&#46; Allelic discrimination was performed using a 7500 Real-Time PCR system &#40;Applied Biosystems&#44; CA&#44; USA&#41; by comparing the fluorescence levels before and after amplification &#40;45 cycles of 15 seconds at 95 &#176;C and 1 min at 60 &#176;C&#41;&#46; Two SNPs &#40;rs7412 and rs429358&#41; were evaluated to determine the <span class="elsevierStyleItalic">APOE</span> genotype&#44; as previously described &#40;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#41;&#46; The real-time PCR reactions were run using the protocol presented above&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">Pearson&#39;s Chi-squared test with simulated <span class="elsevierStyleItalic">p</span>-values was used to compare the genotype distributions between cases and controls&#46; The interactions between the <span class="elsevierStyleItalic">GSK3B</span>&#44; <span class="elsevierStyleItalic">GAB2</span> and <span class="elsevierStyleItalic">SORL1</span> SNPs and <span class="elsevierStyleItalic">APOE&#8727;4</span> were tested in two ways&#58; first&#44; each group was stratified into <span class="elsevierStyleItalic">APOE&#8727;4</span>-positive and <span class="elsevierStyleItalic">APOE&#8727;4</span>-negative subgroups&#44; and the association between each SNP and the diagnosis of AD was assessed separately in each group&#46; In the second step&#44; a binomial logistic regression model was used to compare the interactions between <span class="elsevierStyleItalic">APOE&#8727;4</span> and each of the three SNPs in the entire sample&#46; The statistical analysis was conducted using R software version 2&#46;12&#46;2&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS AND DISCUSSION</span><p id="para70" class="elsevierStylePara elsevierViewall">Our results are consistent with the well-established role of the <span class="elsevierStyleItalic">APOE&#8727;4</span> allele as a risk factor for sporadic AD &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#44; <a class="elsevierStyleCrossRef" href="#bib5">5</a>&#44; <a class="elsevierStyleCrossRef" href="#bib6">6</a>&#44; <a class="elsevierStyleCrossRefs" href="#bib23">23-25</a>&#41;&#40;7&#41;&#46; Data regarding the genetics of AD in the Brazilian population remain scarce &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#44; <a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&#44; underscoring the importance of our findings&#46; We call attention to the positive association of all the studied SNPs&#44; namely <span class="elsevierStyleItalic">GAB2</span> rs2373115&#44; <span class="elsevierStyleItalic">GSK3B</span> rs6438552 and <span class="elsevierStyleItalic">SORL1</span> rs641120&#44; with AD &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#41;&#46; The association of the GG genotype of <span class="elsevierStyleItalic">SORL1</span> with AD &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;047&#44; OR&#8202;&#61;&#8202;2&#46;07&#44; CI<span class="elsevierStyleInf">95&#37;</span> &#91;1&#46;17 - 3&#46;68&#93;&#41; was independent of <span class="elsevierStyleItalic">APOE</span>&#44; and the binomial logistic regression analysis showed no interaction effect between <span class="elsevierStyleItalic">APOE&#8727;4</span> and any of the <span class="elsevierStyleItalic">SORL1</span> genotypes &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46; We conclude that <span class="elsevierStyleItalic">SORL1</span> has an independent role in AD&#44; irrespective of the presence of the <span class="elsevierStyleItalic">APOE&#8727;4</span> allele&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl2"></elsevierMultimedia><p id="para80" class="elsevierStylePara elsevierViewall">We found a positive association between the GG genotype of <span class="elsevierStyleItalic">GAB2</span> &#40;rs2373115&#41; and the diagnosis of AD &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;021&#44; OR&#8202;&#61;&#8202;1&#46;8&#44; CI95&#37; &#91;1&#46;01-3&#46;18&#93;&#41;&#46; This genotype was associated with a greater odds ratio &#40;OR&#41; for AD in the <span class="elsevierStyleItalic">APOE&#8727;4</span> carriers &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;006&#44; OR&#8202;&#61;&#8202;5&#46;08&#44; CI<span class="elsevierStyleInf">95&#37;</span> &#91;1&#46;45-18&#46;98&#93;&#41;&#46; We further used logistic regression to investigate the interaction between the <span class="elsevierStyleItalic">APOE&#8727;4</span> and <span class="elsevierStyleItalic">GAB2</span> polymorphisms &#40;GG vs&#46; non-GG genotypes&#44; given the small proportion of individuals with the TT genotype in our sample&#41;&#44; and we observed a robust increase in the effect as a result of the interaction between <span class="elsevierStyleItalic">GAB2</span> GG and <span class="elsevierStyleItalic">APOE&#8727;4</span> &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;014&#44; OR<span class="elsevierStyleInf">interaction</span>&#8202;&#61;&#8202;7&#46;95&#44; OR<span class="elsevierStyleInf">main</span>&#8202;&#61;&#8202;1&#46;44&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">With respect to the association between the <span class="elsevierStyleItalic">GSK3B</span> polymorphism &#40;rs6438552&#41; and AD diagnosis&#44; we found that the GG genotype was approximately twice as common in the AD group &#40;28&#46;8&#37;&#41; than in the controls &#40;13&#46;8&#37;&#41; and that this genotype had a significant effect on the OR &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;018&#44; OR&#8202;&#61;&#8202;2&#46;48&#44; CI<span class="elsevierStyleInf">95&#37;</span> &#91;1&#46;19-5&#46;20&#93;&#41;&#46; Interestingly&#44; this effect was even more pronounced in the absence of <span class="elsevierStyleItalic">APOE&#8727;4</span> &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;003&#44; OR&#8202;&#61;&#8202;4&#46;45&#44; CI<span class="elsevierStyleInf">95&#37;</span> &#91;1&#46;47-16&#46;39&#93;&#41;&#46; In contrast&#44; the A allele was associated with a protective effect&#44; irrespective of the <span class="elsevierStyleItalic">APOE</span> status &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;018&#44; OR&#8202;&#61;&#8202;0&#46;40&#44; CI<span class="elsevierStyleInf">95&#37;</span> &#91;0&#46;19-0&#46;84&#93;&#41;&#59; however&#44; the logistic regression analysis showed that <span class="elsevierStyleItalic">APOE&#8727;4</span>-positive carriers of the AA genotype displayed an increased OR for AD &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;024&#44; OR<span class="elsevierStyleInf">interaction</span>&#8202;&#61;&#8202;1&#46;10&#44; OR<span class="elsevierStyleInf">main</span>&#8202;&#61;&#8202;0&#46;19&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46; This finding is noteworthy because it indicates that the A allele of the <span class="elsevierStyleItalic">GSK3B</span> gene may represent either a protective factor or a risk factor for AD&#44; depending on the <span class="elsevierStyleItalic">APOE</span> genotype&#46; We speculate that this dual role may occur because the rs6438552 polymorphism is intronic and may affect the transcription and splicing of <span class="elsevierStyleItalic">GSK3B</span>&#46; In fact&#44; splice variants of <span class="elsevierStyleItalic">GSK3B</span> arising from the AA genotype have been shown to favor Tau protein hyperphosphorylation&#44; which is one of the pathological hallmarks of AD &#40;<a class="elsevierStyleCrossRef" href="#bib28">28</a>&#41;&#46;</p><p id="para100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">APOE&#8727;4</span> is involved in the abnormal cleavage of the amyloid-precursor protein &#40;APP&#41;&#44; leading to the accumulation of the amyloid-beta peptide&#44; which in turn favors the hyperphosphorylation of Tau&#46; These pathological changes ultimately disrupt axonal transport and neuronal viability &#40;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#44; <a class="elsevierStyleCrossRef" href="#bib30">30</a>&#41;&#46; <span class="elsevierStyleItalic">GAB2</span> and <span class="elsevierStyleItalic">GSK3B</span> &#40;rs6438552&#44; AA genotype&#41; have been shown to increase Tau phosphorylation &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#44; <a class="elsevierStyleCrossRef" href="#bib28">28</a>&#41;&#46; The studied <span class="elsevierStyleItalic">GSK3B</span> and <span class="elsevierStyleItalic">GAB2</span> polymorphisms are located in intronic regions of these genes and may thus have subtle effects on transcription&#44; with biological consequences that are yet to be defined&#46; It is also possible that these SNPs are in linkage disequilibrium with other polymorphisms that may contribute to the observed effects&#46; GAB2 is a scaffolding protein with important roles in several growth and differentiation signaling pathways&#44; including the phosphorylation of kinases that participate in core neurobiological pathways related to AD &#40;<a class="elsevierStyleCrossRefs" href="#bib15">15&#44;16&#44;31&#44;32</a>&#41;&#46; GAB2 and presenilin 1 both activate PI3K&#44; leading to the activation of PKB and the further inactivation of GSK3B &#40;<a class="elsevierStyleCrossRef" href="#bib33">33</a>&#41;&#46; Because the inactivation of GSK3B prevents Tau hyperphosphorylation in neurons &#40;<a class="elsevierStyleCrossRef" href="#bib34">34</a>&#41;&#44; it is reasonable to assume that any decrease in <span class="elsevierStyleItalic">GAB2</span> expression and&#47;or function would increase Tau phosphorylation &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; Supporting this hypothesis&#44; <span class="elsevierStyleItalic">in vitro</span> studies have shown that the inhibition of <span class="elsevierStyleItalic">GAB2</span> expression using siRNA increases Tau phosphorylation &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">We conclude that interactions between the <span class="elsevierStyleItalic">GAB2</span> and <span class="elsevierStyleItalic">GSK3B</span> polymorphisms and the well-established genetic factor <span class="elsevierStyleItalic">APOE</span> may modify the overall risk of AD&#46; These effects are by no means linear or cumulative&#44; given that the protective effect of a one studied polymorphism &#40;e&#46;g&#46;&#44; the AA genotype of <span class="elsevierStyleItalic">GSK3B</span>&#41; may increase the odds ratio for AD in the presence of <span class="elsevierStyleItalic">APOE&#8727;4</span>&#46; Our results support the hypothesis that there is no single genetic cause for late-onset AD&#59; instead&#44; the development of AD depends on the interaction of several genes&#44; environmental factors and age&#46; Further evaluation of the interactions between distinct genes and of the respective implications on neuronal homeostasis may provide insight into the complex neurobiology of AD&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        1 => array:2 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
        ]
        2 => array:2 [
          "identificador" => "cesec30"
          "titulo" => "RESULTS AND DISCUSSION"
        ]
        3 => array:2 [
          "identificador" => "xack639462"
          "titulo" => "ACKNOWLEDGMENTS"
        ]
        4 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
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    "tienePdf" => true
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara40" class="elsevierStyleSimplePara elsevierViewall">In this study&#44; we investigated the associations between single-nucleotide polymorphisms in <span class="elsevierStyleItalic">GAB2</span> &#40;rs2373115&#41;&#44; <span class="elsevierStyleItalic">GSK3B</span> &#40;rs6438552&#41; and <span class="elsevierStyleItalic">SORL1</span> &#40;rs641120&#41; and Alzheimer&#8217;s disease &#40;AD&#41;&#44; both alone and in combination with the <span class="elsevierStyleItalic">APOE&#8727;4</span> allele&#46;</p></span>"
      ]
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    "NotaPie" => array:1 [
      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara" id="cenpara20">No potential conflict of interest was reported&#46;</p> <p class="elsevierStyleNotepara" id="cenpara30">All authors contributed to the present work and consent to the publication of the findings&#46; Gattaz WF and Ojopi EB were responsible for the initial concept&#46; The patients were recruited by Bertolucci PHF&#44; Forlenza OV and Gattaz WF&#46; The experimental analyses were performed by Izzo G and Kerr DS&#46; The statistical analyses were performed by Santos B and Kerr DS&#46; Izzo G wrote the first draft of the manuscript&#46; The literature review was performed by by Izzo G and Kerr DS&#46; The manuscript was prepared and formatted and the tables were prepared by Kerr DS and Forlenza OV&#46; All authors have reviewed and approved the final manuscript&#46;</p>"
      ]
    ]
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      0 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">The OR for <span class="elsevierStyleItalic">APOE</span> was calculated by comparing <span class="elsevierStyleItalic">APOE&#8727;4</span> carriers with non-carriers&#46; The ORs for other genes compared the homozygous risk allele genotype with the remaining cohort &#40;e&#46;g&#46;&#44; GG vs&#46; GT &#43; TT&#41;&#46;</p>"
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                  \t\t\t\t" scope="col">Gene&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">DbSNP rs ID&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Risk Allele&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Freq&#46; Cases&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Freq&#46; Controls&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">OR &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>-value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">APOE</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">429358 7412&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">E4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&#46;33 &#40;1&#46;73-6&#46;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">GAB2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2373115&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">G&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">1&#46;79 &#40;1&#46;01-3&#46;18&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;021&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">5&#46;08 &#40;1&#46;45-18&#46;98&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;65&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;211&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;19&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;024<a class="elsevierStyleCrossRef" href="#tfn2">&#8727;</a>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">SORL1</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">641120&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;140&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">5&#46;39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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              "nota" => "<p class="elsevierStyleNotepara" id="cenpara10"><span class="elsevierStyleItalic">p</span>&#60;0&#46;05&#46; The OR interaction values were obtained by logistic regression evaluating the interaction between <span class="elsevierStyleItalic">APOE</span>&#8727;4 and the given genotype&#46; &#8225; Because there were very few individuals who were homozygous for the T allele&#44; this interaction was discarded&#46;</p>"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Logistic regression analysis of the risk genotype for <span class="elsevierStyleItalic">LOAD</span> in <span class="elsevierStyleItalic">APOE&#8727;4</span> individuals&#46;</p>"
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                0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                  "host" => array:1 [
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                      "Revista" => array:5 [
                        "tituloSerie" => "Science"
                        "fecha" => "2003"
                        "volumen" => "302"
                        "numero" => "5646"
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              "etiqueta" => "2"
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                      "titulo" => "Role of genes and environments for explaining Alzheimer disease"
                      "autores" => array:1 [
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                          "etal" => true
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                  "host" => array:1 [
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                      "doi" => "10.1001/archpsyc.63.1.74"
                      "Revista" => array:6 [
                        "tituloSerie" => "Archives of general psychiatry"
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                        "volumen" => "63"
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                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16389200"
                            "web" => "Medline"
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            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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                          "etal" => true
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                          "etal" => true
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                  "contribucion" => array:1 [
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Article information

ISSN: 18075932
Original language: English

DOI:10.6061/clinics/2013(02)RC01

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