ABSTRACT
We studied the association between clinical outcome in MS and allelic variants single nucleotide polymorphisms (SNPs) of interleukin-1alpha (IL-1alpha), IL-1beta and a variable number tandem repeat (VNTR) in IL-1 receptor antagonist (IL-1RN). A total of 377 patients with MS were studied. Significant associations between IL-1 genotypes and clinical outcome were found using logistic regression after correction for gender, onset age and disease duration. The same trends were subsequently demonstrated in a second independent group of 67 primary progressive patients. Our results suggest that genetically determined immunomodulation mediated by IL-1 influences long-term prognosis in multiple sclerosis (MS).
Subject(s)
Adjuvants, Immunologic/genetics , Genetic Predisposition to Disease/genetics , Interleukin-1/genetics , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Polymorphism, Genetic/genetics , Sialoglycoproteins/genetics , Adult , Age of Onset , Case-Control Studies , Disease Progression , Female , Gene Frequency/genetics , Genotype , Homozygote , Humans , Interleukin 1 Receptor Antagonist Protein , Interleukin-1/immunology , Linkage Disequilibrium/genetics , Male , Middle Aged , Multiple Sclerosis/physiopathology , Polymorphism, Genetic/immunology , Sex Factors , Sialoglycoproteins/immunologyABSTRACT
BACKGROUND: Oxidative stress has been implicated in inflammatory demyelination. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1/GSTT1), encode low activity variants (GSTP1), or are associated with variable inducibility (GSTM3). OBJECTIVES: To investigate the association between clinical outcome in MS and allelic variants of GSTM1, GSTM3, GSTT1, and GSTP1. METHODS: Four hundred patients with clinically definite MS were studied. Disability was measured using the Kurtzke Expanded Disability Status Scale (EDSS). Disability was graded as mild (EDSS 0-4), moderate (4.5-5.5), or severe (EDSS 6-10). PCR-based genotyping was performed using DNA extracted from lymphocytes. Significant associations between GST genotypes and clinical outcome were corrected for gender, onset age, and disease duration using logistic regression. RESULTS: We found that the GSTM3 AA genotype was associated with severe disability in patients with a disease duration of more than 10 years (p = 0.027, n = 177, OR = 2.4, 95% CI = 1.1-5.0). Homozygosity for both GSTM1*0 and GSTP1*Ile105 containing allele was associated with severe disability in patients with a disease duration greater than 10 years (p = 0.022, n = 179, OR = 5.0, 95% CI = 1.3-19.8). CONCLUSIONS: Our results suggest that long-term prognosis in MS is influenced by a genetically determined ability to remove the toxic products of oxidative stress.
Subject(s)
Disability Evaluation , Glutathione Transferase/genetics , Multiple Sclerosis/genetics , Multiple Sclerosis/physiopathology , Polymorphism, Genetic/genetics , Adult , Age of Onset , Female , Genotype , Humans , Male , Middle AgedABSTRACT
Unlike other areas of rehabilitation, which typically follow a single incident such as trauma or stroke and are followed by improvement (or at least an expectation of stable impairment), multiple sclerosis (MS) presents the problem of progressive impairment and disability. In addition the nature and course of this progression are variable, so that the population is heterogeneous. Expectations for outcome must be modest, and measurement should be focused on quality on life issues. On a background of pre-existing complex disability, multiple single-case (before and after) study designs often present the best evidence for effectiveness of the team approach and for specific interventions. This evidence is presented and reviewed.
