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Article ; Online: Blood type gene locus has no influence on ACE association with Alzheimer's disease.

Braae, Anne / Medway, Christopher / Carrasquillo, Minerva / Younkin, Steven / Kehoe, Patrick G / Morgan, Kevin

2015 Volume 36, Issue 4, Page(s) 1767.e1–1767.e2

Abstract: The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually ... ...

Abstract	The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD.
MeSH term(s)	ABO Blood-Group System/genetics ; Alzheimer Disease/genetics ; Genetic Association Studies ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Haplotypes ; Humans ; Peptidyl-Dipeptidase A/blood ; Peptidyl-Dipeptidase A/genetics ; Risk Factors
Chemical Substances	ABO Blood-Group System ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2015.01.013
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Article ; Online: An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALM isoform.

Parikh, Ishita / Medway, Christopher / Younkin, Steven / Fardo, David W / Estus, Steven

Molecular neurodegeneration

2014 Volume 9, Page(s) 32

Abstract: Background: Although genome wide studies have associated single nucleotide polymorphisms (SNP)s near PICALM with Alzheimer's disease (AD), the mechanism underlying this association is unclear. PICALM is involved in clathrin-mediated endocytosis and ... ...

Abstract	Background: Although genome wide studies have associated single nucleotide polymorphisms (SNP)s near PICALM with Alzheimer's disease (AD), the mechanism underlying this association is unclear. PICALM is involved in clathrin-mediated endocytosis and modulates Aß clearance in vitro. Comparing allelic expression provides the means to detect cis-acting regulatory polymorphisms. Thus, we evaluated whether PICALM showed allele expression imbalance (AEI) and whether this imbalance was associated with the AD-associated polymorphism, rs3851179. Results: We measured PICALM allelic expression in 42 human brain samples by using next-generation sequencing. Overall, PICALM demonstrated equal allelic expression with no detectable influence by rs3851179. A single sample demonstrated robust global PICALM allelic expression imbalance (AEI), i.e., each of the measured isoforms showed AEI. Moreover, the PICALM isoform lacking exons 18 and 19 (D18-19 PICALM) showed significant AEI in a subset of individuals. Sequencing these individuals and subsequent genotyping revealed that rs588076, located in PICALM intron 17, was robustly associated with this imbalance in D18-19 PICALM allelic expression (p = 9.54 x 10-5). This polymorphism has been associated previously with systolic blood pressure response to calcium channel blocking agents. To evaluate whether this polymorphism was associated with AD, we genotyped 3269 individuals and found that rs588076 was modestly associated with AD. However, when both the primary AD SNP rs3851179 was added to the logistic regression model, only rs3851179 was significantly associated with AD. Conclusions: PICALM expression shows no evidence of AEI associated with rs3851179. Robust global AEI was detected in one sample, suggesting the existence of a rare SNP that strongly modulates PICALM expression. AEI was detected for the D18-19 PICALM isoform, and rs588076 was associated with this AEI pattern. Conditional on rs3851179, rs588076 was not associated with AD risk, suggesting that D18-19 PICALM is not critical in AD. In summary, this analysis of PICALM allelic expression provides novel insights into the genetics of PICALM expression and AD risk.
MeSH term(s)	Aged, 80 and over ; Alleles ; Allelic Imbalance/genetics ; Alzheimer Disease/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Introns/genetics ; Male ; Monomeric Clathrin Assembly Proteins/genetics ; Polymorphism, Single Nucleotide ; Protein Isoforms/genetics ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Monomeric Clathrin Assembly Proteins ; PICALM protein, human ; Protein Isoforms
Language	English
Publishing date	2014-08-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/1750-1326-9-32
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Article ; Online: Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism.

Pardiñas, Antonio F / Nalmpanti, Mariana / Pocklington, Andrew J / Legge, Sophie E / Medway, Christopher / King, Adrian / Jansen, John / Helthuis, Marinka / Zammit, Stanley / MacCabe, James / Owen, Michael J / O'Donovan, Michael C / Walters, James T R

The American journal of psychiatry

2019 Volume 176, Issue 6, Page(s) 477–486

Abstract: Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may ... ...

Abstract	Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.
MeSH term(s)	Adult ; Antipsychotic Agents/therapeutic use ; Clozapine/analogs & derivatives ; Clozapine/metabolism ; Clozapine/therapeutic use ; Coffee ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1A2/genetics ; Drug Interactions ; Female ; Genome-Wide Association Study ; Glucuronosyltransferase/genetics ; Humans ; Male ; Pharmacogenomic Variants ; Polymorphism, Single Nucleotide ; Schizophrenia/drug therapy ; Nicotiana
Chemical Substances	Antipsychotic Agents ; Coffee ; bilirubin glucuronoside glucuronosyltransferase ; norclozapine (1I9001LWY8) ; CYP1A1 protein, human (EC 1.14.14.1) ; CYP1A2 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP1A2 (EC 1.14.14.1) ; UGT2B10 protein, human (EC 2.4.1.-) ; Glucuronosyltransferase (EC 2.4.1.17) ; Clozapine (J60AR2IKIC)
Language	English
Publishing date	2019-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	280045-7
ISSN	1535-7228 ; 0002-953X
ISSN (online)	1535-7228
ISSN	0002-953X
DOI	10.1176/appi.ajp.2019.18050589
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Article ; Online: A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia.

Hall, Lynsey S / Medway, Christopher W / Pain, Oliver / Pardiñas, Antonio F / Rees, Elliott G / Escott-Price, Valentina / Pocklington, Andrew / Bray, Nicholas J / Holmans, Peter A / Walters, James T R / Owen, Michael J / O'Donovan, Michael C

Human molecular genetics

2019 Volume 29, Issue 1, Page(s) 159–167

Abstract: Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on ... ...

Abstract	Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.43 × 10-6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia.
MeSH term(s)	Brain/metabolism ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Humans ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; Schizophrenia/genetics ; Schizophrenia/pathology ; Transcriptome/genetics
Language	English
Publishing date	2019-11-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddz253
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Article ; Online: Using Fisher's method with PLINK 'LD clumped' output to compare SNP effects across Genome-wide Association Study (GWAS) datasets.

Shi, Hui / Medway, Christopher / Brown, Kristelle / Kalsheker, Noor / Morgan, Kevin

International journal of molecular epidemiology and genetics

2010 Volume 2, Issue 1, Page(s) 30–35

Abstract: Unlabelled: As the number of publically available GWAS datasets continues to grow, bioinformatic tools which enable routine manipulation of data are becoming increasingly useful. Meta-analysis using multiple GWAS datasets has become essential to ... ...

Abstract	Unlabelled: As the number of publically available GWAS datasets continues to grow, bioinformatic tools which enable routine manipulation of data are becoming increasingly useful. Meta-analysis using multiple GWAS datasets has become essential to elucidate novel SNP associations which may not be readily discovered in each GWAS individually due to insufficient power. Replication of GWAS findings is critical and is the 'arbiter' of genuine SNP associations. We have developed an 'LD aware' bioinformatics application which allows efficient comparison of SNP effects across multiple GWAS datasets using Fisher's combined probability test from PLINK (v1.06) 'LD clumped' output. Availability: the application is freely available from the authors.
Language	English
Publishing date	2010-11-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2553441-5
ISSN	1948-1756 ; 1948-1756
ISSN (online)	1948-1756
ISSN	1948-1756
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Article ; Online: The vitamin D receptor gene is associated with Alzheimer's disease.

Lehmann, Donald J / Refsum, Helga / Warden, Donald R / Medway, Christopher / Wilcock, Gordon K / Smith, A David

Neuroscience letters

2011 Volume 504, Issue 2, Page(s) 79–82

Abstract: Vitamin D may have a role in brain function. Low levels have been frequently associated with cognitive decline and may contribute to diseases of the nervous system. The vitamin D receptor (VDR) is widely expressed in human brain. Vitamin D appears to be ... ...

Abstract	Vitamin D may have a role in brain function. Low levels have been frequently associated with cognitive decline and may contribute to diseases of the nervous system. The vitamin D receptor (VDR) is widely expressed in human brain. Vitamin D appears to be neuroprotective and may regulate inflammation in the brain. We examined two VDR polymorphisms, Apa1 and Taq1. We used DNA from 255 Alzheimer's disease (AD) cases and 260 cognitively screened elderly controls from the longitudinal cohort of the Oxford Project to Investigate Memory and Ageing (OPTIMA). The presence of each of the linked alleles, Apa1 T and Taq1 G, was associated with the risk of AD, particularly in people <75 years old: odds ratios ≥3.0 and p≤0.005. We also found preliminary evidence of interactions associated with AD between these polymorphisms and two other genes involved in the regulation of inflammation, interleukin-10 (IL10) and dopamine β-hydroxylase (DBH): synergy factors ≥3.4, uncorrected p<0.05. These associations are biologically plausible and are consistent with a role for vitamin D in AD. Nevertheless, we consider this to be a hypothesis-generating study, which needs to be replicated in a larger dataset.
MeSH term(s)	Alleles ; Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Cohort Studies ; DNA/genetics ; Dopamine beta-Hydroxylase/genetics ; Humans ; Inflammation/genetics ; Interleukin-10/genetics ; Odds Ratio ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Receptors, Calcitriol/genetics ; Risk
Chemical Substances	Apolipoproteins E ; Receptors, Calcitriol ; Interleukin-10 (130068-27-8) ; DNA (9007-49-2) ; Dopamine beta-Hydroxylase (EC 1.14.17.1)
Language	English
Publishing date	2011-09-03
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2011.08.057
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Article ; Online: Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array.

Barber, Imelda S / Braae, Anne / Clement, Naomi / Patel, Tulsi / Guetta-Baranes, Tamar / Brookes, Keeley / Medway, Christopher / Chappell, Sally / Guerreiro, Rita / Bras, Jose / Hernandez, Dena / Singleton, Andrew / Hardy, John / Mann, David M / Morgan, Kevin

Neurobiology of aging

2016 Volume 49, Page(s) 215.e1–215.e8

Abstract: We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals ... ...

Abstract	We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.
MeSH term(s)	Alzheimer Disease/genetics ; DNA Mutational Analysis/methods ; Genetic Association Studies ; Genetic Predisposition to Disease/genetics ; Genetic Testing ; Genetic Variation/genetics ; Humans ; Oligonucleotide Array Sequence Analysis/methods ; Parkinson Disease/genetics ; Ubiquitin-Protein Ligases/genetics ; tau Proteins/genetics
Chemical Substances	MAPT protein, human ; tau Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27)
Language	English
Publishing date	2016-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2016.09.008
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Article ; Online: Analysis of Genome-Wide Association Study (GWAS) data looking for replicating signals in Alzheimer's disease (AD).

Shi, Hui / Medway, Christopher / Bullock, James / Brown, Kristelle / Kalsheker, Noor / Morgan, Kevin

International journal of molecular epidemiology and genetics

2009 Volume 1, Issue 1, Page(s) 53–66

Abstract: We have performed cross-platform comparisons of output from 4 GWAS in late-onset Alzheimer's disease (LOAD) - Reiman et al., 2007; Li et al., 2008; Beecham et al., 2008 and Carrasquillo et al., 2009 to search for new association signals. The aim was to ... ...

Abstract	We have performed cross-platform comparisons of output from 4 GWAS in late-onset Alzheimer's disease (LOAD) - Reiman et al., 2007; Li et al., 2008; Beecham et al., 2008 and Carrasquillo et al., 2009 to search for new association signals. The aim was to reveal genes that replicated across studies and hence merit further investigation. All SNPs with p-values ranging between 5×10(-5) - 5×10(-8) from each study were assessed across the other studies (either directly or by using a perfect proxy when comparing data from different chip platforms). This revealed only a single SNP (rs929156 in the tripartite motif-containing protein 15, TRIM15, gene) that was replicating across all studies at a level approaching genome-wide significance (P = 8.77×10(-8)) and where meta-analysis of odds ratios showed a significant effect on risk (OR 1.1, 95% Cl 1.0-1.2, P = 0.03). The vast majority of data analysed failed to replicate across these GWAS. The number of replicating association signals we observed is no higher than would be expected due to chance. However, increasing the power by using additional data from larger studies may enable this approach to identify potential LOAD candidate genes for confirmatory association studies.
Language	English
Publishing date	2009-11-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2553441-5
ISSN	1948-1756 ; 1948-1756
ISSN (online)	1948-1756
ISSN	1948-1756
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Article ; Online: Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia.

Malik, Manasi / Chiles, Joe / Xi, Hualin S / Medway, Christopher / Simpson, James / Potluri, Shobha / Howard, Dianna / Liang, Ying / Paumi, Christian M / Mukherjee, Shubhabrata / Crane, Paul / Younkin, Steven / Fardo, David W / Estus, Steven

Human molecular genetics

2015 Volume 24, Issue 12, Page(s) 3557–3570

Abstract: The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) ... ...

Abstract	The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.
MeSH term(s)	Aged ; Aged, 80 and over ; Alleles ; Alternative Splicing ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Antibodies, Monoclonal, Humanized/pharmacology ; Cell Line ; Exons ; Female ; Gene Expression ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Humans ; Introns ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Male ; Polymorphism, Single Nucleotide ; RNA Stability ; RNA, Messenger/genetics ; Sialic Acid Binding Ig-like Lectin 3/antagonists & inhibitors ; Sialic Acid Binding Ig-like Lectin 3/genetics ; Sialic Acid Binding Ig-like Lectin 3/metabolism
Chemical Substances	Antibodies, Monoclonal, Humanized ; CD33 protein, human ; RNA, Messenger ; Sialic Acid Binding Ig-like Lectin 3 ; lintuzumab (V00Y10W60W)
Language	English
Publishing date	2015-03-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddv092
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Article ; Online: Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease.

Barber, Imelda S / García-Cárdenas, Jennyfer M / Sakdapanichkul, Chidchanok / Deacon, Christopher / Zapata Erazo, Gabriela / Guerreiro, Rita / Bras, Jose / Hernandez, Dena / Singleton, Andrew / Guetta-Baranes, Tamar / Braae, Anne / Clement, Naomi / Patel, Tulsi / Brookes, Keeley / Medway, Christopher / Chappell, Sally / Mann, David M / Morgan, Kevin

Neurobiology of aging

2015 Volume 39, Page(s) 220.e1–7

Abstract: Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor ... ...

Abstract	Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed.
MeSH term(s)	Aged ; Alzheimer Disease/genetics ; Amyloid beta-Protein Precursor/genetics ; Base Pairing/genetics ; Cohort Studies ; Exons/genetics ; Female ; Gene Deletion ; Gene Frequency ; Genetic Association Studies ; Genetic Testing ; Humans ; Introns/genetics ; Male ; Middle Aged ; Mutation ; Sequence Analysis, DNA
Chemical Substances	Amyloid beta-Protein Precursor
Language	English
Publishing date	2015-12-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2015.12.011
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