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Jorge R Oksenberg

Publications and source records attributed to Jorge R Oksenberg.

At least 19 recordsLinked to original sources
PubMed2005

Modular transcriptional activity characterizes the initiation and progression of autoimmune encephalomyelitis.

Murine experimental autoimmune encephalomyelitis is a well-established model that recapitulates many clinical and physiopathological aspects of multiple sclerosis (MS). An important conceptual development in the understanding of both experimental autoimmune encephalomyelitis and MS pathogenesis has been the compartmentalization of the mechanistic process into two distinct but overlapping and connected phases, inflammatory and neurodegenerative. However, the dynamics of CNS transcriptional changes that underlie the development and regression of the phenotype are not well understood. Our report presents the first high frequency longitudinal study looking at the earliest transcriptional changes in the CNS of NOD mice immunized with myelin oligodendrocyte glycoprotein 35-55 in CFA. Microarray-based gene expression profiling and histopathological analysis were performed from spinal cord samples obtained at 13 time points around the first clinical symptom (every other day until day 11 and every day onward until day 19 postimmunization). Advanced statistics and data-mining algorithms were used to identify expression signatures that correlated with disease stage and histological profiles. Discrete phases of neuroinflammation were accompanied by distinctive expression signatures, in which altered immune to neural gene expression ratios were observed. By using high frequency gene expression analysis we captured expression profiles that were characteristic of the transition from innate to adaptive immune response in this experimental paradigm between days 11 and 12 postimmunization. Our study demonstrates the utility of large-scale transcriptional studies and advanced data mining to decipher complex biological processes such as those involved in MS and other neurodegenerative disorders.

Adjuvants, Immunologic↗
PubMed2005

Genomics and new targets for multiple sclerosis.

Compelling epidemiological and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how MS individuals respond to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and environmental influences. Equally significant, it is likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others.

Animals↗
PubMed2004

Transcription-based prediction of response to IFNbeta using supervised computational methods.

Changes in cellular functions in response to drug therapy are mediated by specific transcriptional profiles resulting from the induction or repression in the activity of a number of genes, thereby modifying the preexisting gene activity pattern of the drug-targeted cell(s). Recombinant human interferon beta (rIFNbeta) is routinely used to control exacerbations in multiple sclerosis patients with only partial success, mainly because of adverse effects and a relatively large proportion of nonresponders. We applied advanced data-mining and predictive modeling tools to a longitudinal 70-gene expression dataset generated by kinetic reverse-transcription PCR from 52 multiple sclerosis patients treated with rIFNbeta to discover higher-order predictive patterns associated with treatment outcome and to define the molecular footprint that rIFNbeta engraves on peripheral blood mononuclear cells. We identified nine sets of gene triplets whose expression, when tested before the initiation of therapy, can predict the response to interferon beta with up to 86% accuracy. In addition, time-series analysis revealed potential key players involved in a good or poor response to interferon beta. Statistical testing of a random outcome class and tolerance to noise was carried out to establish the robustness of the predictive models. Large-scale kinetic reverse-transcription PCR, coupled with advanced data-mining efforts, can effectively reveal preexisting and drug-induced gene expression signatures associated with therapeutic effects.

Adolescent↗
PubMed2004

Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping.

To explore the potential value of recently developed high-density linkage mapping methods in the analysis of complex disease we have regenotyped five nuclear families first studied in the 1996 UK multiple sclerosis linkage genome screen, using Applied Biosystems high-density microsatellite linkage mapping set, the Illumina BeadArray linkage mapping panel (version 3) and the Affymetrix GeneChip Human Mapping 10K array. We found that genotyping success, information extraction and genotyping accuracy were improved with all systems. These improvements were particularly marked with the SNP-based methods (Illumina and Affymetrix), with little difference between these. The extent of additional information extracted is considerable, indicating that reanalysis of existing multiplex families using these newer systems would substantially increase power.

Chromosome Mapping↗
PubMed2004

Methods for high-density admixture mapping of disease genes.

Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) has been proposed as an efficient approach to localizing disease-causing variants that differ in frequency (because of either drift or selection) between two historically separated populations. Near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the alleles derived from the ethnic group that carries more disease-susceptibility alleles. The central attraction of admixture mapping is that, since gene flow has occurred recently in modern populations (e.g., in African and Hispanic Americans in the past 20 generations), it is expected that admixture-generated linkage disequilibrium should extend for many centimorgans. High-resolution marker sets are now becoming available to test this approach, but progress will require (a). computational methods to infer ancestral origin at each point in the genome and (b). empirical characterization of the general properties of linkage disequilibrium due to admixture. Here we describe statistical methods to estimate the ancestral origin of a locus on the basis of the composite genotypes of linked markers, and we show that this approach accurately estimates states of ancestral origin along the genome. We apply this approach to show that strong admixture linkage disequilibrium extends, on average, for 17 cM in African Americans. Finally, we present power calculations under varying models of disease risk, sample size, and proportions of ancestry. Studying approximately 2500 markers in approximately 2500 patients should provide power to detect many regions contributing to common disease. A particularly important result is that the power of an admixture mapping study to detect a locus will be nearly the same for a wide range of mixture scenarios: the mixture proportion should be 10%-90% from both ancestral populations.

Alleles↗
PubMed2004

Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis.

A large body of research supports a multifactorial cause in multiple sclerosis (MS), with an underlying genetic susceptibility likely acting in concert with undefined environmental exposures. Here, we used a highly efficient multilocus genotyping assay to study single nucleotide polymorphisms representing variation in 34 genes from inflammatory pathways in a well-characterized MS familial data set. Evidence of transmission distortion was present for several polymorphisms. Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained significant after correction for multiple testing and were reproduced in a second independent African American MS data set. In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families. Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility.

Adult↗
PubMed2004

Re: GAMES issue.

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Europe↗
PubMed2003

Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.

An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.

Alleles↗
PubMed2003

Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study.

Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.

Chromosomes, Human, Pair 1↗
PubMed2002

Multiple susceptibility loci for multiple sclerosis.

Multiple sclerosis (MS) is a common and frequently disabling autoimmune disorder mediated by autoaggressive T cells and autoantibodies that target central nervous system myelin. While numerous studies have demonstrated a strong genetic component to MS, it has been difficult to identify the specific genes involved. Several genomic screens have been undertaken to locate such genes, but have not provided consistent gene localization, except for the MHC on chromosome 6p21 and a locus on chromosome 19q13. To determine which of the original genomic locations presented in the US genome screen could be replicated, a more detailed analysis of additional families was performed. The results, derived from a population of 266 affected individuals belonging to 98 multiplex families, continue to support linkage to chromosomes 6p21, 6q27, and 19q13 with LOD scores>3.0, and suggest that regions on chromosomes 12q23-24 and 16p13 may also harbor susceptibility loci for MS. Analysis taking into account the known HLA-DR2 association identified two additional potential linkage regions on chromosomes 7q21-22 and 13q33-34. These regions can now be targeted for detailed study to identify the underlying MS susceptibility genes.

Chromosomes, Human, Pair 13↗
PubMed2002

Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P=.005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P=.03), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P=.02).

Adolescent↗
PubMed2002

Gene expression analysis reveals altered brain transcription of glutamate receptors and inflammatory genes in a patient with chronic focal (Rasmussen's) encephalitis.

Chronic focal encephalitis (CFE) generally presents with seizures that increase in severity and frequency as the disease progresses. Malfunction of synaptic transmission through altered glutamate signaling has been proposed as a likely mechanism triggering CFE. In addition, profuse inflammation is commonly seen in histopathological examination of resected tissue. To further explore the roles of glutamatergic activity and inflammation in this disease, we examined the expression of 52 genes by real time RT-PCR (kinetic RT-PCR or kRT-PCR) in a brain specimen from a CFE patient with active seizures, eight control specimens from patients with several other neurologic disorders, and two from individuals with no recorded history of neurological abnormalities. The CFE specimen displayed a dramatic increase in the expression of several inflammation-related genes (i.e. IL1 beta, IgVH, and IL2R gamma among others) and a striking down-regulation of several GluRs, in particular mGluR4. This type of analysis may prove useful in describing the molecular events underlying intractable epilepsy.

Adult↗
PubMed2002

The HLA locus and multiple sclerosis in Spain. Role in disease susceptibility, clinical course and response to interferon-beta.

The HLA-DR2 haplotype (DRB1*1501, DQB1*0602) on chromosome 6p21 has consistently demonstrated both association and linkage with multiple sclerosis (MS) in case-control and family studies, particularly in Caucasians of Northern European descent. However, the role of a gene within this region in determining clinical features or response to immunotherapy remains largely unknown. A new familial MS data set from the Mediterranean Spanish Basin was collected according to rigorous ascertainment criteria. We confirm, primarily in the cohort originating from Continental Spain, that similar to other high-risk groups, there was a significant association with HLA-DR2. No other DR or DQ alleles were found to be associated with disease susceptibility nor were alleles at the class I A and B loci. Overall, the effect of HLA appears to be less substantial than that observed in a reference US population with a higher disease incidence. No effect of the HLA-DR2 haplotype on age of onset, initial clinical symptoms and disease course was observed. Similarly, no difference in the distribution of responders and nonresponders to interferon-beta (IFNB) therapy, as defined by primary and secondary end points, was observed when individuals were stratified according to HLA-DR2 status.

Adult↗