Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multi-centre case-control study

A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE e4 dosage.

The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS)

Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus

Nicastrin (NCSTN) is a component of the ?-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued ?-secretase activity and amyloid beta (Aß) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.

A multi-center study of ACE and the risk of late-onset Alzheimer's disease

A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-ß (Aß) peptide. Thus, altered Aß degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aß-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.

Formação, aprendizagem e organizações aprendentes

Numa era de grande mudança a todos níveis, como seja o aparecimento constante de tecnologia que permite o acesso à informação, todos os indivíduos, qualquer que seja o seu grão de formação inicial, devem estar atentos e manter-se actualizados, é uma questão de sobrevivência.

Retaining repatriates: an exploratory study in portuguese companies

This study aims to understand the factors which may explain the retention of repatriates from companies acting within Portugal. These factors can be related either to the individual, or to the work, to the organisation or to non-working contexts. Eight companies located in Portugal have participated in this study. Several semi-structured interviews were done to 16 organizational representatives and to 28 repatriates. The obtained results show that the repatriates’ retention on the visited companies may be influenced by several categories of factors. We can conclude that it is (1) the good relation with the leadership, (2) the recognition of the performed job but, also (3) the seniority, (4) the age and the (5) depressed national job market. These are the major factors that emerge as relevant factors for the retention. Hence, there is not only one category of explaining determining factors for the retention decision, but there are several. These findings will be discussed in detail and implications and suggestions for future research will be proposed as well.

Certificación de las normas ISO-9000 aplicado a la industria manufacturera del ramo de la electrónica

Tesis (Maestría en Ciencias de la Administración con Especialidad en Producción y Calidad) UANL

Guía para la creación de un programa de marketing organizado en torno a las necesidades y objetivos de las pequeñas y medianas empresas

Tesis (Maestría en Ciencias de la Administración con Especialidad en Relaciones Industriales) UANL

Amor y erotismo en la poesía de David Huerta : lectura de historia

Tesis (Maestría en Letras Españolas) UANL

Resultado de un programa informativo de VIH

Tesis (Maestría en Ciencias de Enfermería con Enfasis en Administración de Servicios) UANL

Cambios en el estilo de vida durante la semana y su relación con el turno de trabajo

Tesis (Maestría en Psicología Social) UANL

Caries dental y diabetes mellitus no insulino dependiente

Tesis (Maestría en Salud Pública con Especialidad en Odontología Social) UANL.

Autoeficacia, asertividad y consumo de tabaco y alcohol en estudiantes de secundaria

Tesis (Maestría en Ciencias de Enfermería con énfasis en Salud Comunitaria) U.A.N.L.

Propuesta de un modelo fiscal régimen de actividades empresariales en relación con el régimen de pequeños contribuyentes para ISR en México

Tesis (Maestría en Contaduría Pública con Especialidad en Impuestos) U.A.N.L.