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Search Results: 1 - 10 of 401307 matches for " Minerva M. Carrasquillo "
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Multiple Insulin Degrading Enzyme Variants Alter In Vitro Reporter Gene Expression
Olivia Belbin, Michael Crump, Gina D. Bisceglio, Minerva M. Carrasquillo, Kevin Morgan, Steven G. Younkin
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021429
Abstract: The insulin degrading enzyme (IDE) variant, v311 (rs6583817), is associated with increased post-mortem cerebellar IDE mRNA, decreased plasma β-amyloid (Aβ), decreased risk for Alzheimer's disease (AD) and increased reporter gene expression, suggesting that it is a functional variant driving increased IDE expression. To identify other functional IDE variants, we have tested v685, rs11187061 (associated with decreased cerebellar IDE mRNA) and variants on H6, the haplotype tagged by v311 (v10; rs4646958, v315; rs7895832, v687; rs17107734 and v154; rs4646957), for altered in vitro reporter gene expression. The reporter gene expression levels associated with the second most common haplotype (H2) successfully replicated the post-mortem findings in hepatocytoma (0.89 fold-change, p = 0.04) but not neuroblastoma cells. Successful in vitro replication was achieved for H6 in neuroblastoma cells when the sequence was cloned 5′ to the promoter (1.18 fold-change, p = 0.006) and 3′ to the reporter gene (1.29 fold change, p = 0.003), an effect contributed to by four variants (v10, v315, v154 and v311). Since IDE mediates Aβ degradation, variants that regulate IDE expression could represent good therapeutic targets for AD.
Evaluation of the Role of SNCA Variants in Survival without Neurological Disease
Michael G. Heckman, Alexandra I. Soto-Ortolaza, Nancy N. Diehl, Minerva M. Carrasquillo, Ryan J. Uitti, Zbigniew K. Wszolek, Neill R. Graff-Radford, Owen A. Ross
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042877
Abstract: Background A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD) is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA) affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease. Methods We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33–99 years) and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk. Results There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021), from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025). A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD. Conclusions In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.
Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study
Minerva M Carrasquillo, Olivia Belbin, Talisha A Hunter, Li Ma, Gina D Bisceglio, Fanggeng Zou, Julia E Crook, V Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, Peter Passmore, Kevin Morgan, for the Alzheimer's Research UK (ARUK) consortium, Steven G Younkin
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-54
Abstract: We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56).Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).Following the identification of the APOE ε4 allele as a risk factor for late-onset Alzheimer's disease (LOAD) in 1993 [1], consistent replication of subsequently identified candidates was not achieved until 2009, when two genome-wide association studies (GWAS) [2,3] identified associations of variants in or near CLU, PICALM , and CR1 with LOAD, which were consistently replicated in multiple large, independent case-control studies [4-17]. Subsequently, a variant near BIN1 was reported [4] to achieve genome-wide significant association in a later GWAS published in 2010 that also replicated well in follow-up studies [14-19]. These results demonstrate the utility of the hypothesis-free GWAS approach for identifying loci that associate with LOAD and the necessity of pooling samples and data from multiple centers to obtain resources with sufficient statistical power (GWAS typically > 14,000, follow-up typically total > 28,000) to detect the modest ORs (e.g. 0.8/1.2) associated with these variants in GWAS and follow-up studies.Two recently published companion s
Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer’s Disease Pathology
Fanggeng Zou, Olivia Belbin, Minerva M. Carrasquillo, Oliver J. Culley, Talisha A. Hunter, Li Ma, Gina D. Bisceglio, Mariet Allen, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium , Kevin Morgan, Steven G. Younkin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064802
Abstract: GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer’s disease (LOAD) with reported odds ratios (ORs) ranging from 0.75–0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61–1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61–0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82–0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10?7?9.3×10?6). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = ?0.34, p = 0.0006) and senile plaque counts (r = ?0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = ?0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level.
LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer’s Disease (LOAD)
Sarah Lincoln, Mariet Allen, Claire L. Cox, Louise P. Walker, Kimberly Malphrus, Yushi Qiu, Thuy Nguyen, Christopher Rowley, Naomi Kouri, Julia Crook, V. Shane Pankratz, Samuel Younkin, Linda Younkin, Minerva Carrasquillo, Fanggeng Zou, Samer O. Abdul-Hay, Wolfdieter Springer, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K. Wszolek, Jada M. Lewis, Dennis Dickson, Neill R. Graff-Radford, Ronald C. Petersen, Elizabeth Eckman, Steven G. Younkin, Nilüfer Ertekin-Taner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064164
Abstract: Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer’s disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ~400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5′UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02–0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.
Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants
Fanggeng Zou equal contributor,High Seng Chai equal contributor,Curtis S. Younkin equal contributor,Mariet Allen equal contributor,Julia Crook,V. Shane Pankratz,Minerva M. Carrasquillo,Christopher N. Rowley,Asha A. Nair,Sumit Middha,Sooraj Maharjan,Thuy Nguyen,Li Ma,Kimberly G. Malphrus,Ryan Palusak,Sarah Lincoln,Gina Bisceglio,Constantin Georgescu,Naomi Kouri,Christopher P. Kolbert,Jin Jen,Jonathan L. Haines,Richard Mayeux,Margaret A. Pericak-Vance,Lindsay A. Farrer,Gerard D. Schellenberg,Alzheimer's Disease Genetics Consortium,Ronald C. Petersen,Neill R. Graff-Radford,Dennis W. Dickson,Steven G. Younkin,Nilüfer Ertekin-Taner
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002707
Abstract: Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n = 197, temporal cortex n = 202) and with other brain pathologies (non–AD, cerebellar n = 177, temporal cortex n = 197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ±100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non–ADs (q<0.05, p = 7.70×10?5–1.67×10?82). Of these, 2,089 were also significant in the temporal cortex (p = 1.85×10?5–1.70×10?141). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10?6). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9–3.3 fold enrichment (p<10?6) of significant cisSNPs with suggestive AD–risk association (p<10?3) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non–CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.
Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications
Mariet Allen, Fanggeng Zou, High Chai, Curtis S Younkin, Richard Miles, Asha A Nair, Julia E Crook, V Pankratz, Minerva M Carrasquillo, Christopher N Rowley, Thuy Nguyen, Li Ma, Kimberly G Malphrus, Gina Bisceglio, Alexandra I Ortolaza, Ryan Palusak, Sumit Middha, Sooraj Maharjan, Constantin Georgescu, Debra Schultz, Fariborz Rakhshan, Christopher P Kolbert, Jin Jen, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Ryan J Uitti, Zbigniew K Wszolek, Owen A Ross, Ronald C Petersen, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, Nilüfer Ertekin-Taner
Molecular Neurodegeneration , 2012, DOI: 10.1186/1750-1326-7-13
Abstract: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.Glutathione S-Transferase (GST) family of genes have been implicated in multiple neuropsychiatric [1-4] and neurodegenerative diseases [5-11]; where altered levels or function of these enzymes is thought to impact levels of oxidative stress and/or inflammation in a way that contributes to disease susceptibility. A linkage locus on chromosome 10q that has been implicated in both Alzheimer's (AD)[11-13] and Parkinson's disease (PD)[13] harbors two GST genes of the omega class: GSTO1 and GSTO2, which are approximately 75 kb apart.GSTOs have enzymatic activities as thioltransferases and dehydroascorbate reductases that promote antioxidant activity and can also function in metabolism of drugs and toxins[14]. Additionally, GSTO1 was shown to promote activation of the pro-inflammatory cytokine, interleukin-1β (IL-1β) by post-translational processing[15]. Given their location and function, they have been studied as candidate genes in AD and PD[5,6,9,11,14,16-18]. Li et al. compared hippocampal gene expression levels in 6 AD vs. 2 control brains and identified significantly lower GSTO1 levels in the AD hippocampi[5]. This group studied
Procedimiento y algoritmo de estimación en modelos multinivel para proporciones
CASTELLS,ERNESTINA; OJEDA,MARIO M.; MONTERO,MINERVA;
Revista Colombiana de Estadística , 2010,
Abstract: this paper describes a procedure for the estimation of fixed and random parameters in multilevel model for proportions. the estimation procedure is developed using iterative generalized least squares. once the model is formulated, we demonstrate that it is possible to apply the asymptotic estimation theory in the framework of the general lineal model. an algorithm to calculate the proposed estimators is elaborated. we illustrate the application using an example of meta-analysis. it is concluded that the proposed procedure can be favorable strategy to do applied research.
Aspectos éticos en la enfermedad de Alzheimer
Morfi Samper,Rosa; Pereira Márquez,Minerva;
Revista Cubana de Enfermer?-a , 2003,
Abstract: individual aging has been present in all periods of social development as a topic of interest for philosophy, art and medicine. however, in modern society, at the beginning of the xxi century, it is observed a singular situation in which persons surpass the chronological barriers man has established as an aging stage, turning population aging into one of the most important challenges for modern society. the importance attained by this population sector demands an increasing moral commitment from health professionals and, in particular, from nurses. a bibliographic review was made to stress the ethical principles ruling the work of the gerontology nurse. the research was carried out from january to july, 2001. the updated national and international literature were reviewed during this period. the ethical principles of nursing connected with the attention to the older adult with alzheimer's disease were similar. these results show that assistance is needed in the aging process and that the nurse characterized by her humanitarianism fulfills faithfully the ethical principles supporting the nursing practice..
PROCEDURE AND ESTIMATION ALGORITHM IN MULTILEVEL MODELS FOR PROPORTIONS PROCEDIMIENTO Y ALGORITMO DE ESTIMACIóN EN MODELOS MULTINIVEL PARA PROPORCIONES
Castells Ernestina,Ojeda Mario M.,Montero Minerva
Revista Colombiana de Estadística , 2010,
Abstract: This paper describes a procedure for the estimation of fixed and random parameters in multilevel model for proportions. The estimation procedure is developed using Iterative Generalized Least Squares. Once the model is formulated, we demonstrate that it is possible to apply the asymptotic estimation theory in the framework of the general lineal model. An algorithm to calculate the proposed estimators is elaborated. We illustrate the application using an example of meta-analysis. It is concluded that the proposed procedure can be favorable strategy to do applied research. En este artículo se describe un procedimiento para la estimación de parámetros fijos y aleatorios en modelos multinivel para proporciones. El procedimiento de estimación se basa en el método de los mínimos cuadrados generalizados. Una vez que se formula el modelo, se demuestra que es posible aplicar la teoría asintótica de estimación en el marco del modelo lineal general. Se elabora un algoritmo que permite calcular los estimadores propuestos. La aplicación se ilustra con un ejemplo de meta-análisis. Se concluye que el procedimiento presentado puede ser una estrategia favorable en investigaciones aplicadas.
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