The relationship of genetic polymorphisms to disease severity of multiple sclerosis.
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 (GSTMI/GSTT1), encode low activity
variants (GSTPI), or are associated with variable inducibility (GSTM3). Interleukin-1 (IL-
1) alpha and beta are cytokines involved in recruitment of inflammatory cells, the process of
inflammation, and blood-brain barrier breakdown and nerve regeneration. Polymorphisms of
both GST and of a complementary interleukin-1 receptor antagonist have been associated
with severity and susceptibility to other inflammatory conditions.
This thesis examines the influence of the GST and IL-1 genes on both the
susceptibility to Multiple Sclerosis (MS), and the course of disease progression.
The population examined consisted of four hundred patients with clinically definite
MS. Disease severity was measured using the Kurtzke Expanded Disability Status Scale
(EDSS), a robust established ranking scale. PCR-based genotyping was performed using
DNA extracted from lymphocytes. Significant associations between genotypes and clinical
outcome were corrected for known demographic factors influencing prognosis, these being;
gender, onset age, and disease duration using the statistical method of logistic regression.
Significant associations, withstanding multiple testing corrections, with certain IL-I
genotypes and disease severity were found. There was also a significant trend with the GST
isoenzymeM 3 that is expressedin nervous tissue.
No robust findings suggest that these genes influence susceptibility to MS, but the
results suggest that long-term prognosis is genetically influenced by the modulation of
inflammatory cytokines and also by the ability to remove the toxic products of oxidative