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A D Roses

Publications and source records attributed to A D Roses.

At least 19 recordsLinked to original sources
PubMed2006

Use of pairwise marker combination and recursive partitioning in a pharmacogenetic genome-wide scan.

The objective of pharmacogenetic research is to identify a genetic marker, or a set of genetic markers, that can predict how a given person will respond to a given medicine. To search for such marker combinations that are predictive of adverse drug events, we have developed and applied two complementary methods to a pharmacogenetic study of the hypersensitivity reaction (HSR) associated with treatment with abacavir, a medicine that is used to treat HIV-infected patients. Our results show that both of these methods can be used to uncover potentially useful predictive marker combinations. The pairwise marker combination method yielded a collection of marker pairs that featured a spectrum of sensitivities and specificities. Recursive partitioning results led to the genetic delineation of multiple risk categories, including those with extremely high and extremely low risk of HSR. These methods can be readily applied in pharmacogenetic candidate gene studies as well as in genome-wide scans.

Adult↗
PubMed2006

Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease).

Safety and efficacy pharmacogenetics can be applied successfully to the drug discovery and development pipeline at multiple phases. We review drug-target screening using high throughput SNP associations with complex diseases testing more than 1,800 candidate targets with approximately 7,000 SNPs. Alzheimer's disease data are provided as an example. The supplementation of target-selected screening with genome-wide SNP association, to also define susceptibility genes and relevant disease pathways for human diseases, is discussed. Applications for determining predictive genetic or genomic profiles, or derived biomarkers, for drug efficacy and safety during clinical development are exemplified by several successful experiments at different phases of development. A Phase I-IIA study of side effects using an oral drug for the treatment of breast cancer is used as an example of early pipeline pharmacogenetics to predict side effects and allow optimization of dosing. References are provided for several other recently published genetic association studies of adverse events during drug development. We illustrate the early identification of gene variant candidates related to efficacy in a Phase IIA obesity drug trial to generate hypotheses for testing in subsequent development. How these genetic data generated in Phase IIA are subsequently incorporated as hypotheses into later Phase clinical protocols is discussed. A Phase IIB clinical trial for Alzheimer's disease is described that exemplifies the major pipeline decision between program attrition and further clinical development. In this case, there was no significant improvement in 511 intention-to-treat patients but, applying a confirmed prognostic biomarker (APOE4) to segment the clinical trial population, all three doses of rosiglitazone demonstrated improvement in patients who did not carry the APOE4 allele. The data for the APOE4 carriers demonstrated no significant improvement but suggested that there may be a need for higher doses. Thus, a development program that would have been terminated progressed to Phase III registration trials based on the results of prospective efficacy pharmacogenetic analyses. The implications of using APOE genotype as a biomarker to predict efficacy and possibly dose, as well as supporting the basic neurobiology and pharmacology that provided the original target validation, is discussed. Citations are provided that support a slow neurotoxic effect over many years of a specific fragment of apoE protein (over-produced by apoE4 substrate compared to apoE3) on mitochondria and the use of rosiglitazone to increase mitochondrial biogenesis and improve glucose utilization. Pharmacogenetics is currently being used across the pipeline to prevent attrition and to create safer and more effective medicines.

Alzheimer Disease↗
PubMed2006

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease.

Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE epsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE epsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE epsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE epsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE epsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

Aged↗
PubMed2004

A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia.

Tranilast (N-(3'4'-demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA)(7)/(TA)(7) genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P=2 x 10(-22)). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.

Dinucleotide Repeats↗
PubMed2004

Identification of a pharmacogenetic effect by linkage disequilibrium mapping.

A practical limitation to the identification of genetic profiles predictive of drug-induced adverse events is the number of patients with the adverse event that can be tolerated before the drug is withdrawn. Whole genome screening for regions of linkage disequilibrium (LD) associated with a particular phenotype may provide the mechanism to rapidly discover specific and sensitive profiles. We have used data from a large phase III clinical trial of tranilast and typed 76 SNPs over a 2.7 megabase region flanking the uridine diphosphate glucuronosyltranserferase 1A1 gene. Three SNPs within one LD block showed strong association with tranilast-induced hyperbilirubinemia (P<10(-13)). Our data illustrated that a genome-wide LD scan of 100,000-200,000 SNPs is sufficient to identify a pharmacogenetic association with a drug-induced adverse event.

Clinical Trials, Phase III as Topic↗
PubMed2004

Further investigation of linkage disequilibrium SNPs and their ability to identify associated susceptibility loci.

There is currently considerable interest in the use of single-nucleotide polymorphisms (SNPs) to map disease susceptibility genes. The success of this method will depend on a number of factors including the strength of linkage disequilibrium (LD) between marker and disease loci. We used a data set of SNP genotypings in the region of the APOE disease susceptibility locus to investigate the likely usefulness of SNPs in case-control studies. Using the estimated haplotype structure surrounding and including the APOE locus, and assuming a codominant disease model, we treated each SNP in turn as if it were a disease susceptibility locus and obtained, for each disease locus and markers, the expected likelihood ratio test (LRT) to assess disease association. We were particularly interested in the power to detect association with the susceptibility polymorphism itself, the power of nearby markers to detect association, and the ability to distinguish between the susceptibility polymorphism and marker loci also showing association. We found that the expected LRT depended critically on disease allele frequencies. For disease loci with a reasonably common allele we were usually able to detect association. However, for only a subset of markers in the close neighbourhood of the disease locus was association detectable. In these cases we were usually, but not always, able to distinguish the disease locus from nearby associated marker loci. For some disease loci, no other loci demonstrated detectable association with the disease phenotype. We conclude that one may need to use very dense SNP maps in order to avoid overlooking polymorphisms affecting susceptibility to a common phenotype.

Alzheimer Disease↗
PubMed2003

Genetic polymorphisms of the N-acetyltransferase genes and risk of Parkinson's disease.

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1 and NAT2. The authors examined NAT1 and NAT2 for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1 or NAT2 SNP or acetylation haplotype (N = 397 families, 1,580 individuals).

Aged↗
PubMed2003

Pharmacogenetics and disease genetics of complex diseases.

Advances in technologies and the availability of a single nucleotide polymorphism (SNP) map are beginning to show the true potential for the human genome project to affect patient healthcare. A whole genome scan, the use of 100000-300000 SNPs across the genome, is now possible. Use of traditional approaches and the whole genome scan will result in identification of disease susceptibility genes and development of many new treatments in the longer term. In the shorter term, the goal will be to predict those patients at risk to experience an adverse reaction or those with a high probability for improved efficacy (i.e. pharmacogenetics). As progress is made in the area of disease genetics and pharmacogenetics, our understanding of disease susceptibility and its interrelationship with drug response will improve, making targeted therapy (i.e. the right drug to the right patient) a reality.

Biotechnology↗
PubMed2003

Apolipoprotein E4 decreases whereas apolipoprotein E3 increases the level of secreted amyloid precursor protein after closed head injury.

Apolipoprotein E (apoE4) and head trauma are important genetic and environmental risk factors for Alzheimer's disease. Furthermore, apoE4 increases both the acute and chronic consequences of head trauma. The latter are associated with the deposition of amyloid-beta, which is particularly elevated in apoE4 subjects. The short-term effects of head injury are associated with transiently increased metabolism of amyloid precursor protein (APP) and its secreted fragment, APPs. In the present study, we examined the possibility that the acute, short-term pathological effects of apoE4 following head trauma and the corresponding neuroprotective effects of apoE3 are related to isoform-specific effects of apoE on APP metabolism. Accordingly, male transgenic mice expressing human apoE3 or apoE4 on a null mouse apoE background and apoE-deficient and control mice were subjected to closed head injury (CHI). The resulting effects on brain APP, and on its secreted products, APPs and secreted product of the alpha-cleavage of APP (APPsalpha) were then determined 24 h following injury. Immunoblotting revealed no significant differences between the basal APP, APPs and APPsalpha levels of the hippocampus or the cortex of the control and the apoE3 and ApoE4 transgenic mice. The apoE-deficient mice also had similar cortical basal levels of APP and its metabolites, whereas their corresponding basal hippocampal APP and APPs levels were lower than those of the other groups. CHI lowered the hipppocampal APPs and APPsalpha levels of the apoE4 transgenic mice, whereas those of the apoE3 transgenic mice and of the control and apoE-deficient mice were not affected by this insult. In contrast, CHI raised the cortical APP and APPs levels of the apoE3 transgenic mice but had no significant effect on those of the other mice groups. These animal model findings suggest that the acute, short-term pathological effects of apoE4 following CHI and the corresponding neuroprotective effects of apoE3 may be mediated by their opposing effects on the expression and cleavage of cortical and hippocampal APP. Similar isoform-specific interactions between apoE and APP may play a role in the acute, short-term effects of head trauma in humans.

Amyloid beta-Protein Precursor↗
PubMed2002

Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.

The apolipoprotein E (apoE) epsilon 4 allele (apoE4) is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A role for apoE in regeneration of synaptic circuitry after neural injury has been shown in several in vitro studies in which apoE3 supports neuronal sprouting better than apoE4. We evaluated sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing apoE3 or apoE4, in which apoE-dependent granule cell mossy fiber sprouting in the presence of apoE4 is only 51% of the level of apoE3. Sprouting supported by apoE4 had a dose response opposite that by supported by apoE3: although increasing E3 expression increased sprouting, increasing E4 expression decreased sprouting, suggesting that the defect in E4 in supporting neuronal sprouting is a gain-of-negative activity. These results may have important pharmacogenomic implications for AD therapies that modulate apoE expression levels.

Alzheimer Disease↗
PubMed2001

Complete genomic screen in Parkinson disease: evidence for multiple genes.

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Adult↗
PubMed2001

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Age of Onset↗
PubMed2001

Pharmacogenetics.

Pharmacogenetics is the variability of drug response due to inherited characteristics in individuals. Drug metabolizing enzymes have been studied for decades, first as chemical reactions and, more recently, as specific polymorphisms of known molecules. With the availability of whole-genome single-nucleotide polymorphism (SNP) maps, it will soon be possible to create an SNP profile for patients who experience adverse events (AEs) or who respond clinically to the medicine (efficacy). Proof-of-principle experiments have demonstrated that high density SNP maps in chromosomal regions of genetic linkage facilitate the identification of susceptibility disease genes. Whole-genome SNP mapping analyses aimed at determining linkage disequilibrium (LD) profiles along an ordered human genome backbone are in progress. SNP 'fingerprints' or SNP PRINTs(sm) will be used to identify patients at greater risk of an AE, or those patients with a greater chance of responding to a medicine. As LD maps for various ethnic populations are constructed, the number of SNPs necessary to measure for an individual will decrease. Standardized pharmacogenetic maps for drug registration and post-marketing surveillance will result in safer, more effective and more cost-efficient medicines. The timing of these pharmacogenetic applications will occur over the next 5 years. In contrast, the benefits of pharmacogenomic applications such as the identification of new tractable targets will not be visible as new medicines for 7-12 years, due to the lengthy drug development and registration processes.

Humans↗
PubMed2001

Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine.

We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.

Alleles↗
PubMed2001

Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion.

The apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. Each apoE isoform is suggested to have differential effects on neuronal repair mechanisms within the CNS. In the present study, APOE genotype influence on the immediate response to injury and subsequent repair process was examined in a line of transgenic APOE mice possessing human APOE gene insertions (epsilon 3 and epsilon 4). Quantification of synaptophysin and GAP-43 immunoreactivity was used to measure the extent of degeneration and regeneration after entorhinal cortex lesion (ECL). Progressive neurodegenerative decline occurred in the ipsilateral dentate gyrus until day 28 post-ECL which was more severe in APOE epsilon 3 mice compared to APOE epsilon 4 mice. By day 90 post-ECL compensatory sprouting and reactive synaptogenesis had taken place in the dentate gyrus of APOE epsilon 3 mice such that GAP-43 and synaptophysin immunoreactivity had returned to prelesion levels. In contrast, APOE epsilon 4 mice displayed significant deficits in synaptophysin and GAP-43 immunostaining compared to the APOE epsilon 3 mice (P < 0.05). Expansion of the inner molecular layer (IML) was used as a measure of the sprouting index from the commissural-associational pathway and by day 90 post-ECL the IML width in APOE epsilon 3 mice had increased by 45% but only 20% in APOE epsilon 4 mice (P < 0.0001). ApoE immunoreactivity was increased within the neuropil and glia to the same extent in APOE epsilon 3 and APOE epsilon 4 mice post-ECL. There was no significant difference in the deposition and clearance of degeneration products between APOE epsilon 3 and epsilon 4 mice post-ECL. These results indicate that neuronal plasticity is impaired in transgenic mice possessing human APOE epsilon 4 alleles compared to APOE epsilon 3. These isoform-specific differences in plasticity may relate to the severity of AD and poor, long-term recovery after head injury in APOE epsilon 4 individuals.

Alzheimer Disease↗
PubMed2000

Phospholemman is a substrate for myotonic dystrophy protein kinase.

The genetic abnormality in myotonic muscular dystrophy, multiple CTG repeats lie upstream of a gene that encodes a novel protein kinase, myotonic dystrophy protein kinase (DMPK). Phospholemman (PLM), a major membrane substrate for phosphorylation by protein kinases A and C, induces Cl currents (I(Cl(PLM))) when expressed in Xenopus oocytes. To test the idea that PLM is a substrate for DMPK, we measured in vitro phosphorylation of purified PLM by DMPK. To assess the functional effects of PLM phosphorylation we compared I(Cl(PLM)) in Xenopus oocytes expressing PLM alone to currents in oocytes co-expressing DMPK, and examined the effect of DMPK on oocyte membrane PLM expression. We found that PLM is indeed a good substrate for DMPK in vitro. Co-expression of DMPK with PLM in oocytes resulted in a reduction in I(Cl(PLM)). This was most likely a specific effect of phosphorylation of PLM by DMPK, as the effect was not present in oocytes expressing a phos(-) PLM mutant in which all potential phosphorylation had been disabled by Ser --> Ala substitution. The biophysical characteristics of I(Cl(PLM)) were not changed by DMPK or by the phos(-) mutation. Co-expression of DMPK reduced the expression of PLM in oocyte membranes, suggesting a possible mechanism for the observed reduction in I(Cl(PLM)) amplitude. These data show that PLM is a substrate for phosphorylation by DMPK and provide functional evidence for modulation of PLM function by phosphorylation.

Animals↗
PubMed2000

The role of apolipoprotein E in Alzheimer's disease: pharmacogenomic target selection.

The association of inheritance of different apolipoprotein E (APOE, gene; apoE, protein) alleles with the risk and rate of onset of Alzheimer's disease (AD) is now well established and widely confirmed. While there are now a collection of hypotheses concerning the specific relationship of APOE polymorphisms to various phenotypic manifestations of AD, no single compelling theory has been tested and universally accepted. The only clear fact emerging during the past 6 years is that differences in APOE genotype affect the average rate of disease onset as a predictable function of the inheritance of this polymorphic gene. Methods now exist to enable experimental designs to study the metabolic effects of inheriting different APOE alleles, addressing what differences that may be present for many years, perhaps over the entire lifetime, can lead to earlier or later manifestations of the disease and are therapeutically tractable. This review summarizes part of an experimental approach to identify biological pathways influenced by the different APOE polymorphisms that are relevant to the pathogenesis of AD.

Alleles↗