Biomedical subjects
Jorge R Oksenberg
Publications and source records attributed to Jorge R Oksenberg.
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.
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.
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.
Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy.
Recent technological breakthroughs allowing for large-scale analysis of gene transcripts and large-scale monitoring of the immune response with protein chips are revealing new participants in the pathogenesis of multiple sclerosis. Some of these participants may be useful targets for therapy.
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).
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.
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.
Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.
Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.
New insights into the genetics of multiple sclerosis.
Tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develop in genetically susceptible individuals after exposure to a causal agent that is yet undefined. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, posttranscriptional regulatory mechanisms, and significant environmental influences. Equally significant is that genetic heterogeneity also likely exists, meaning that specific genes influence susceptibility and pathogenesis in some affecteds but not in others. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen significant progress in the developments of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and to define the pathological basis of demyelination. These developments have set the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. The identification and characterization of the genes are likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.